Endothelin antagonists

ABSTRACT

A compound of the formula (I):or a pharmaceutically acceptable salt thereof is disclosed, as well as processes for and intermediates in the preparation thereof, and a method of antagonizing endothelin.

This application is a division of Ser. No. 08/905,913 filed Aug. 4, 1997now U.S. Pat. No. 6,162,927 continuation-in-part application U.S. patentapplication Ser. No. 08/794,506, filed Feb. 4, 1997, abandoned which isa continuation-in-part of U.S. patent application Ser. No. 08/600,625,filed Feb. 13, 1996, abandoned which is a continuation-in-part of U.S.patent application Ser. No. 08/497,998, filed Aug. 2, 1995, abandonedwhich is a continuation-in-part of U.S. patent application Ser. No.08/442,575, filed May 30, 1995, now U.S. Pat. No. 5,767,144, which is acontinuation-in-part of U.S. patent application Ser. No. 08/334,717,filed Nov. 4, 1994, abandoned which is a continuation-in-part of U.S.patent application Ser. No. 08/293,349, filed Aug. 19, 1994, abandoned.

TECHNICAL FIELD

The present invention relates to compounds which are endothelinantagonists, processes for making such compounds, syntheticintermediates employed in these processes and methods and compositionsfor antagonizing endothelin.

BACKGROUND OF THE INVENTION

Endothelin (ET) is a 21 amino acid peptide that is produced byendothelial cells. ET is produced by enzymatic cleavage of a Trp-Valbond in the precursor peptide big endothelin (Big ET). This cleavage iscaused by an endothelin converting enzyme (ECE). Endothelin has beenshown to constrict arteries and veins, increase mean arterial bloodpressure, decrease cardiac output, increase cardiac contractility invitro, stimulate mitogenesis in vascular smooth muscle cells in vitro,contract non-vascular smooth muscle including guinea pig trachea, humanurinary bladder strips and rat uterus in vitro, increase airwayresistance in vivo, induce formation of gastric ulcers, stimulaterelease of atrial natriuretic factor in vitro and in vivo, increaseplasma levels of vasopressin, aldosterone and catecholamines, inhibitrelease of renin in vitro and stimulate release of gonadotropins invitro.

It has been shown that vasoconstriction is caused by binding ofendothelin to its receptors on vascular smooth muscle (Nature 332 411(1988), FEBS Letters 231 440 (1988) and Biochem. Biophys. Res. Commun.154 868 (1988)). An. agent which suppresses endothelin production or anagent which binds to endothelin or which inhibits the binding ofendothelin to an endothelin receptor will produce beneficial effects ina variety of therapeutic areas. In fact, an anti-endothelin antibody hasbeen shown, upon intrarenal infusion, to ameliorate the adverse effectsof renal ischemia on renal vascular resistance and glomerular filtrationrate (Kon, et al., J. Clin. Invest. 83 1762 (1989)). In addition, ananti-endothelin antibody attenuated the nephrotoxic effects ofintravenously administered cyclosporin (Kon, et al., Kidney Int. 37 1487(1990)) and attenuated infarct size in a coronary arteryligation-induced myocardial infarction model (Watanabe, et al., Nature344 114 (1990)).

Clozel et al. (Nature 365: 759-761 (1993)) report that Ro 46-2005, anonpeptide ET-A/B antagonist, prevents post-ischaemic renalvasoconstriction in rats, prevents the decrease in cerebral blood flowdue to subarachnoid hemorrhage (SAH) in rats, and decreases MAP insodium-depleted squirrel monkeys when dosed orally. A similar effect ofa linear tripeptide-like ET-A antagonist, BQ-485, on arterial caliberafter SAH has also been recently reported (S. Itoh, T. Sasaki, K. Ide,K. Ishikawa, M. Nishikibe, and M. Yano, Biochem. Biophys. Res. Comm. ,195: 969-75 (1993). These results indicate that agents which antagonizeET/ET receptor binding will provide therapeutic benefit in the indicateddisease states.

Agents with the ability to antagonize ET/ET receptor binding have beenshown to be active in a number of animal models of human disease. Forexample, Hogaboam et al (EUR. J. Pharmacol. 1996, 309, 261-269), haveshown that an endothelin receptor antagonist reduced injury in a ratmodel of colitis. Aktan et al (Transplant Int 1996, 9, 201-207) havedemonstrated that a similar agent prevents ischemia-reperfusion injuryin kidney transplantation. Similar studies have suggested the use ofendothelin antagonists in the treatment of angina, pulmonaryhypertension, Raynaud's disease, and migraine. (Ferro and Webb, Drugs1996, 51, 12-27).

Abnormal levels of endothelin or endothelin receptors have also beenassociated with a number of disease states, including prostate cancer(Nelson et al, Nature Medicine 1995, 1, 944-949), suggesting a role ofendothelin in the pathophysiology of these diseases.

Wu-Wong et al (Lfe Sciences 1996, 58, 1839-1847) have shown hat bothendothelin and endothelin antagonists bind tightly to plasma proteins,e.g., serum albumin. This plasma protein binding can decrease theeffectiveness with which the antagonists inhibit endothelin's action.Thus, endothelin antagonists with reduced plasma protein binding may bemore effective than highly bound congeners.

DISCLOSURE OF THE INVENTION

In accordance with the present invention there are compounds of theformula (I):

wherein

Z is —C(R₁₈)(R₁₉)— or —C(O)— wherein R₁₈ and R₁₉ are independentlyselected from hydrogen and loweralkyl;

n is 0 or 1;

R is —(CH₂)_(m)—W wherein m is an integer from 0 to 6 and W is

(a) —C(O)₂—G wherein G is hydrogen or a carboxy protecting group,

(b) —PO₃H₂,

(c) —P(O)(OH)E wherein E is hydrogen, loweralkyl or arylalkyl,

(d) —CN,

(e) —C(O)NHR₁₇ wherein R₁₇ is loweralkyl,

(f) alkylaminocarbonyl,

(g) dialkylaminocarbonyl,

(h) tetrazolyl,

(i) hydroxy,

(j) alkoxy,

(k) sulfonamido,

(l) —C(O)NHS(O)₂R₁₆ wherein R₁₆ is loweralkyl, haloalkyl, aryl ordialkylamino,

(m) —S(O)₂NHC(O)R₁₆ wherein R₁₆ is defined as above,

R₁ and R₂ are independently selected from hydrogen, loweralkyl, alkenyl,alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl,haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl,cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl,dialkylaminocarbonylalkyl, aminocarbonylalkenyl,alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl,aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl,(N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic,(heterocyclic)alkyl and (R_(aa))(R_(bb))N—R_(cc)— wherein R_(aa) is arylor arylalkyl, R_(bb) is hydrogen or alkanoyl and R_(cc) is alkylene,with the proviso that one or both of R₁ and R₂ is other than hydrogen;

R₃ is (a) R₄—C(O)—R₅—, R₄—R_(5a)—, R₄—C(O)—R₅—N(R₆)—, R₆—S(O)₂—R₇— orR₂₆—S(O)—R₂₇—

wherein R₅ is (i) a covalent bond, (ii) alkylene, (iii) alkenylene, (iv)—N(R₂₀)—R₈— or —R_(8a)—N(R₂₀)—R₈— wherein R₈ and R_(8a) areindependently selected from the group consisting of alkylene andalkenylene and R₂₀ is hydrogen, loweralkyl, alkenyl, haloalkyl,alkoxyalkyl, haloalkoxyalkyl, cylcoalkyl or cycloalkylalkyl or (v)—O—R₉— or —R_(9a)—O—R₉— wherein R₉ and R_(9a) are independently selectedfrom alkylene;

R_(5a) is (i) alkylene or (ii) alkenylene;

R₇ is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or (iv)—N(R₂₁)—R₁₀— or —R_(10a)—N(R₂₁)—R₁₀— wherein R₁₀ and R_(10a) areindependently selected from the group consisting of alkylene andalkenylene and R₂₁ is hydrogen, loweralkyl, alkenyl, haloalkyl,alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl;

R₄ and R₆ are independently selected from the group consisting of

(i) (R₁₁)(R₁₂)N— wherein R₁₁ and R₁₂ are independently selected from

(1) hydrogen,

(2) loweralkyl,

(3) haloalkyl,

(4) alkoxyalkyl,

(5) haloalkoxyalkyl,

(6) alkenyl,

(7) alkynyl,

(8) cycloalkyl,

(9) cycloalkylalkyl,

(10) aryl,

(11) heterocyclic,

(12) arylalkyl,

(13) (heterocyclic)alkyl,

(14) hydroxyalkyl,

(1 5) alkoxy,

(16) aminoalkyl,

(17) trialkylaminoalkyl,

(18) alkylaminoalkyl,

(19) dialkylaminoalkyl, and

(20) carboxyalky₁,

(ii) loweralkyl,

(iii) alkenyl,

(iv) alkynyl,

(v) cycloalkyl,

(vi) cycloalkylalkyl,

(vii) aryl,

(viii) arylalkyl,

(ix) heterocyclic,

(x) (heterocyclic)alkyl,

(xi) alkoxyalkyl,

(xii) hydroxyalkyl,

(xiii) haloalkyl,

(xiv) haloalkenyl,

(xv) haloalkoxyalkyl,

(xvi) haloalkoxy,

(xvii) alkoxyhaloalkyl,

(xviii) alkylaminoalkyl,

(xix) dialkylaminoalkyl,

(xx) alkoxy, and

 wherein z is 0-5 and R_(7a) is alkylene;

R₂₆ is (i) loweralkyl, (ii) haloalkyl, (iii) alkenyl, (iv) alkynyl, (v)cycloalkyl, (vi) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, (ix)heterocyclic, (x) (heterocyclic)alkyl, (xi) alkoxyalkyl or (xii)alkoxy-substituted haloalkyl; and

R₂₇ is alkylene or alkenylene;

(b) R₂₂—O—C(O)—R₂₃— wherein R₂₂ is a carboxy protecting group orheterocyclic and R₂₃ is (i) a covalent bond, (ii) alkylene, (iii)alkenylene or (iv) —N(R₂₄)—R₂₅—wherein R₂₅ is alkylene and R₂₄ ishydrogen or loweralkyl,

(c) loweralkyl,

(d) alkenyl,

(e) alkynyl,

(f) cycloalkyl,

(g) cycloalkylalkyl,

(h) aryl,

(i) arylalkyl,

(j) aryloxyalkyl,

(k) heterocyclic,

(l) (heterocyclic)alkyl,

(m) alkoxyalkyl,

(n) alkoxyalkoxyalkyl, or

(o) R₁₃—C(O)—CH(R₁₄)—

 wherein R₁₃ is amino, alkylamino or dialkylamino and R₁₄ is aryl orR₁₅—C(O)— wherein R₁₅ is amino, alkylamino or dialkylamino;

or a pharmaceutically acceptable salt thereof.

A preferred embodiment of the invention is a compound of formula (II)

wherein the substituents —R₂, —R and —R₁ exist in a trans,transrelationship and Z, n, R, R₁, R₂, and R₃ are as defined above.

Another preferred embodiment of the invention is a compound of formula(I) or (II) wherein n is 0 and Z is —CH₂—.

Another preferred embodiment of the invention is a compound of formula(I) or (II) wherein n is 1 and Z is —CH₂—.

Another preferred embodiment of the invention is a compound of formula(I) or (II) wherein n is 0, Z is —CH₂—, and R₃ is R₄—C(O)—R₅—,R₆—S(O)₂—R₇— or R₂₆—S(O)—R₂₇— wherein R₄, R₅, R₆, R₇, R₂₆ and R₂₇ are asdefined above.

Another preferred embodiment of the invention is a compound of formula(I) or (II) wherein n is 0, Z is —CH₂—, and R₃ is alkoxyalkyl oralkoxyalkoxyalkyl.

A more preferred embodiment of the invention is a compound of formula(I) or (II) wherein n is 0, Z is —CH₂—, and R₃ is R₄—C(O)—R₅— wherein R₄is (R₁₁)(R₁₂)N— as defined above and R₅ is alkylene or R₃ isR₆—S(O)₂—R₇— or R₂₆—S(O)—R₂₇— wherein R₇ is alkylene, R₂₇ is alkyleneand R₆ and R₂₆ are defined as above.

Another more preferred embodiment of the invention is a compound offormula (I) or (II) wherein n is 0, Z is —CH₂— and R₃ isR₄—C(O)—N(R₂₀)—R₈— or R₆—S(O)₂—N(R₂₁)—R₁₀— wherein R₈ and R₁₀ arealkylene and R₄, R₆, R₂₀ and R₂₁ are defined as above.

An even more preferred embodiment of the invention is a compound offormula (I) or (II) wherein n is 0, R is tetrazolyl or —C(O)₂—G whereinG is hydrogen or a carboxy protecting group or R is tetrazolyl or R is—C(O)—NHS(O)₂R₁₆ wherein R₁₆ is loweralkyl, haloalkyl or aryl, Z is—CH₂—,

R₁ and R₂ are independently selected from (i) loweralkyl, (ii)cycloalkyl, (iii) substituted aryl wherein aryl is phenyl substitutedwith one, two or three substituents independently selected fromloweralkyl, alkoxy, halo, alkoxyalkoxy and carboxyalkoxy, (iv)substituted or unsubstituted heterocyclic, (v) alkenyl, (vi)heterocyclic (alkyl), (vii) arylalkyl, (viii) aryloxyalkyl, (ix)(N-alkanoyl-N-alkyl)aminoalkyl and (x) alkylsulfonylamidoalkyl, and R₃is R₄—C(O)—R₅— wherein R₄ is (R₁₁)(R₁₂)N— wherein R₁₁ and R₁₂ areindependently selected from loweralkyl, haloalkyl, alkoxyalkyl,haloalkoxyalkyl, aryl, arylalkyl, heterocyclic, hydroxyalkyl, alkoxy,aminoalkyl, and trialkylaminoalkyl, and R₅ is alkylene; or R₃ isR₄—C(O)—N(R₂₀)—R₈— or R₆—S(O)₂—N(R₂₁)—R₁₀— wherein R₄ is loweralkyl,aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and R₆ is loweralkyl,haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl, R₈ and R₁₀are alkylene and R₂₀ and R₂₁ are loweralkyl; or R₃ is R₆—S(O)₂—R₇— orR₂₆—S(O)—R₂₇— wherein R₆ is loweralkyl or haloalkyl, R₇ is alkylene, R₂₆is loweralkyl and R₂₇ is alkylene.

A yet more preferred embodiment of the invention is a compound offormula (I) or (II) wherein n is 0, R is —C(O)₂—G wherein G is hydrogenor a carboxy protecting group, tetrazolyl or —C(O)—NHS(O)₂R₁₆ whereinR₁₆ is loweralkyl, haloalkyl or aryl, Z is —CH₂—, R₁ is (i) loweralkyl,(ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi)pyridyl, (vii) furanyl, (viii) substituted or unsubstituted4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl,4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl,4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl,3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl,4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanylor dihydrobenzofuranyl wherein the substituent is selected from alkoxy,alkoxyalkoxy and carboxyalkoxy, (ix) heterocyclic (alkyl), (x)arylalkyl, (xi) aryloxyalkyl, (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or(xiii) alkylsulfonylamidoalkyl, R₂ is substituted or unsubstituted1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl,8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl,4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R₃is R₄—C(O)—N(R₂₀)—R₈— or R₆—S(O)₂—N(R₂₁)—R₁₀— wherein R₈ and R₁₀ arealkylene, R₂₀ and R₂₁ are loweralkyl, R₄ is loweralkyl, aryl, alkoxy,alkylamino, aryloxy or arylalkoxy and R₆ is loweralkyl, haloalkyl,alkoxyalkyl, aryl or arylalkyl.

Another yet more preferred embodiment of the invention is a compound offormula (I) or (II) wherein n is 0, R is —C(O)₂—G wherein G is hydrogenor a carboxy protecting group, tetrazolyl or —C(O)—NHS(O)₂R₁₆ whereinR₁₆ is loweralkyl, haloalkyl or aryl, Z is —CH₂—, R₁ is (i) loweralkyl,(ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi)pyridyl, (vii) furanyl, (viii) substituted or unsubstituted4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl,4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl,4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl,3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl,4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanylor dihydrobenzofuranyl wherein the substituent is selected from alkoxy,alkoxyalkoxy and carboxyalkoxy, (ix) heterocyclic (alkyl), (x)arylalkyl, (xi) aryloxyalkyl, (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or(xiii) alkylsulfonylamidoalkyl, R₂ is substituted or unsubstituted1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl,8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl,4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R₃is R₄—C(O)—R₅— wherein R₅ is alkylene and R₄ is (R₁₁)(R₁₂)N— wherein R₁₁and R₁₂ are independently selected from loweralkyl, haloalkyl,alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heterocyclic,hydroxyalkyl, alkoxy, aminoalkyl, and trialkylaminoalkyl.

Another yet more preferred embodiment of the invention is a compound offormula (I) or (II) wherein n is 0, R is —C(O)₂—G wherein G is hydrogenor a carboxy protecting group, tetrazolyl or —C(O)—NHS(O)₂R₁₆ whereinR₁₆ is loweralkyl, haloalkyl or aryl, Z is —CH₂—, R₁ is (i) loweralkyl,(ii) alkenyl, (iii) heterocyclic (alkyl), (iv) aryloxyalkyl, (v)arylalkyl, (vi) aryl, (vii) (N-alkanoyl-N-alkyl)aminoalkyl, or (viii)alkylsulfonylamidoalkyl, R₂ is substituted or unsubstituted1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl,8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl,4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl whereinthe substituent is selected from loweralkyl, alkoxy and halogen and R₃is R₄—C(O)—R₅— wherein R₅ is alkylene and R₄ is (R₁₁)(R₁₂)N— wherein R₁₁is loweralkyl and R₁₂ is aryl, arylalkyl, hydroxyalkyl, alkoxy,aminoalkyl, trialkylaminoalkyl, or heterocyclic.

Another yet more preferred embodiment of the invention is a compound offormula (I) or (II) wherein n is 0, R is —C(O)₂—G wherein G is hydrogenor a carboxy protecting group, tetrazolyl or —C(O)—NHS(O)₂R₁₆ whereinR₁₆ is loweralkyl, haloalkyl or aryl, Z is —CH₂—, R₁ is (i) loweralkyl,(ii) alkenyl, (iii) heterocyclic (alkyl), (iv) aryloxyalkyl, (v)arylalkyl, (vi) (N-alkanoyl-N-alkyl)aminoalkyl, or (vii)alkylsulfonylamidoalkyl,(vii) phenyl, or (ix) substituted orunsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl,3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl,1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein thesubstituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxyand carboxyalkoxy, R₂ is substituted or unsubstituted 1,3-benzodioxolyl,7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl,8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl,dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituentis selected from loweralkyl, alkoxy and halogen and R₃ isR₆—S(O)₂—N(R₂₁)—R₁₀— wherein R₁₀ is alkylene, R₆ is loweralkyl,haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl and R₂₁ isloweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl.

Another yet more preferred embodiment of the invention is a compound offormula (I) or (II) wherein n is 0, R is —C(O)₂—G wherein G is hydrogenor a carboxy protecting group, tetrazolyl or —C(O)—NHS(O)₂R₁₆ whereinR₁₆ is loweralkyl, haloalkyl or aryl, Z is —CH₂—, R₁ is (i) substitutedor unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl,3-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4-methoxymethoxyphenyl,1,3-benzodioxolyl or 1,4-benzodioxanyl wherein the substituent isselected from loweralkyl, haloalkyl, alkoxy and alkoxyalkoxy, (ii)loweralkyl, (iii) alkenyl, (iv) heterocyclic (alkyl), (v) aryloxyalkyl,(vi) arylalkyl, (vii) (N-alkanoyl-N-alkyl)aminoalkyl, (viii)alkylsulfonylamidoalkyl,or (ix) phenyl, R₂ is substituted orunsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl,1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl,4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl whereinthe substituent is selected from loweralkyl, alkoxy and halogen and R₃is alkoxycarbonyl or R₆—S(O)₂—N(R₂₁)—R₁₀— wherein R₁₀ is alkylene, R₆ isloweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R₂₁ isloweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl.

Another yet more preferred embodiment of the invention is a=compound offormula (I) or (II) wherein n is 0, R is —C(O)₂—G wherein G is hydrogenor a carboxy protecting group, tetrazolyl or —C(O)—NHS(O)₂R₁₆ whereinR₁₆ is loweralkyl or haloalkyl, Z is —CH₂—, R₁ is loweralkyl,alkenyl,heterocyclic (alkyl), aryloxyalkyl, aryalkyl, aryl,(N-alkanoyl-N-alkyl)aminoalkyl, or alkylsulfonylamidoalkyl, and R₃ isR₄—C(O)—R₅— wherein R₅ is alkylene and R₄ is (R₁₁)(R₁₂)N— wherein R₁₁and R₁₂ are independently selected from alkyl, aryl, hydroxyalkyl,alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic.

A still more preferred embodiment of the invention is a compound offormula (I) or (II) wherein n is 0, R is —C(O)₂—G wherein G is hydrogenor a carboxy protecting group, tetrazolyl or —C(O)—NHS(O)₂R₁₆ whereinR₁₆ is loweralkyl or haloalkyl, Z is —CH₂—, R₁ is substituted orunsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl,4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl,4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl,1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein thesubstituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy,(ii) loweralkyl, (iii) alkenyl, (iv) heterocyclic (alkyl), (v)aryloxyalkyl, (vi) arylalkyl, (vii) (N-alkanoyl-N-alkyl)aminoalkyl,(viii) alkylsulfonylamidoalkyl,or (ix) phenyl, R₂ is 1,3-benzodioxolyl,1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl,dimethoxyphenyl, fluorophenyl or difluorophenyl and R₃ is R₄—C(O)—R₅—wherein R₅ is alkylene and R₄ is (R₁₁)(R₁₂)N— wherein R₁₁ and R₁₂ areindependently selected from loweralkyl, aryl, arylalkyl, hydroxyalkyl,alkoxy, aminoalkyl, trialkylaminoalkyl, or heterocyclic.

Another still more preferred embodiment of the invention is a compoundof formula (I) or (II) wherein n is 0, R is —C(O)₂—G wherein G ishydrogen or a carboxy protecting group, tetrazolyl or —C(O)—NHS(O)₂R₁₆wherein R₁₆ is loweralkyl or haloalkyl, Z is —CH₂—, R₁ is loweralkyl,alkenyl, heterocyclic (alkyl), aryloxyalkyl, arylalkyl,(N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, phenyl, oralkoxyalkyl, R₂ is 1,3-benzodioxolyl, 1,4-benzodioxanyl,dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl,fluorophenyl or difluorophenyl and R₃ is R₄—C(O)—R₅— wherein R₅ isalkylene and R₄ is (R₁₁)(R₁₂)N— wherein R₁₁ and R₁₂ are independentlyselected from loweralkyl, aryl, arylalkyl, hydroxyalkyl, alkoxy,aminoalkyl, trialkylaminoalkyl, or heterocyclic.

A most highly preferred embodiment of the invention is a compound offormula (I) or (II) wherein n is 0, R is —C(O)₂—G wherein G is hydrogenor a carboxy protecting group, Z is —CH₂—, R₁ is substituted orunsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl,4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl,4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl,1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein thesubstituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R₂is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl,benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl ordifluorophenyl and R₃ is R₄—C(O)—R₅— wherein R₅ is alkylene and R₄ is(R₁₁)(R₁₂)N— wherein R₁₁ and R₁₂ are independently selected fromloweralkyl.

Another most highly preferred embodiment of the invention is a compoundof formula (I) or (II) wherein n is 0, R is —C(O)₂—G wherein G ishydrogen or a carboxy protecting group, Z is —CH₂—, R₁ is substituted orunsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl,4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl,4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl,1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein thesubstituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R₂is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl,benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl ordifluorophenyl and R₃ is R₄—C(O)—R₅— wherein R₅ is alkylene and R₄ is(R₁₁)(R₁₂)N— wherein R₁l is loweralkyl and R₁₂ is aryl.

Another most highly preferred embodiment of the invention is a compoundof formula (I) or (II) wherein n is 0, R is —C(O)₂—G wherein G ishydrogen or a carboxy protecting group, Z is —CH₂—, R₁ is substituted orunsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl,2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4-methoxymethoxyphenyl,1,3-benzodioxolyl, 1,4-benzodioxany(or dihydrobenzofuranyl wherein thesubstituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxyand carboxyalkoxy, R₂ is substituted or unsubstituted 1,3-benzodioxolyl,7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl,8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl,dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituentis selected from loweralkyl, alkoxy and halogen and R₃ isR₆—S(O)₂—N(R₂₁)—R₁₀— wherein R₁₀ is alkylene, R₆ is loweralkyl,haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R₂₁ is loweralkyl,haloalkyl or alkoxyalkyl.

Another most highly preferred embodiment of the invention is a compoundof formula (I) or (II) wherein n is 0, R is —C(O)₂—G wherein G ishydrogen or a carboxy protecting group, Z is —CH₂—, R₁ is substituted orunsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl,2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4-methoxymethoxyphenyl,1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein thesubstituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxyand carboxyalkoxy, R₂ is substituted or unsubstituted 1,3-benzodioxolyl,7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl,8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl,dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituentis selected from loweralkyl, alkoxy and halogen and R₃ is R₄—C(O)—R₅—wherein R₅ is alkylene and R₄ is (R₁₁)(R₁₂)N— wherein R₁₁ is alkyl andR₁₂ is selected from aryl, aminoalkyl, trialkylaminoalkyl, andheterocyclic.

Another most highly preferred embodiment of the invention is a compoundof formula (I) or (II) wherein n is 0, R is —C(O)₂—G wherein G ishydrogen or a carboxy protecting group, Z is —CH2—, R₁ isloweralkyl,alkenyl, heterocyclic (alkyl), aryloxyalkyl, aryalkyl, aryl,(N-alkanoyl-N-alkyl)aminoalkyl, or alkylsulfonylamidoalkyl, and R₃ isR₄—C(O)—R₅— wherein R₅ is alkylene and R₄ is (R₁₁)(R₁₂)N— wherein R₁₁and R₁₂ are independently selected from alkyl, aryl, hydroxyalkyl,alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic, with theproviso that one or R₁₁ and R₁₂ is alkyl.

Another most highly preferred embodiment of the invention is a compoundof formula (I) or (II) wherein n is 0, Z is —CH₂—, and R₃ is R₄—C(O)—R₅—wherein R₄ is (R₁₁)(R₁₂)N— as defined therein and R₅ is alkylene.

Another most highly preferred embodiment of the invention is a compoundof formula (I) or (II) wherein n is 0, Z is —CH₂—, R₁ is loweralkyl, andR₃ is R₄—C(O)—R₅— wherein R₄ is (R₁₁)(R₁₂)N— as defined therein and R₅is alkylene.

Another most highly preferred embodiment of the invention is a compoundof formula (I) or (II) wherein n is 0, Z is —CH₂—, R₁ is alkenyl, and R₃is R₄—C(O)—R₅— wherein R₄ is (R₁₁)(R₁₂)N— as defined therein and R₅ isalkylene.

Another most highly preferred embodiment of the invention is a compoundof formula (I) or (II) wherein n is 0, Z is —CH₂—, R₁ is heterocyclic(alkyl), and R₃ is R₄—C(O)—R₅— wherein R₄ is (R₁₁)(R₁₂)N— as definedtherein and R₅ is alkylene.

Another most highly preferred embodiment of the invention is a compoundof formula (I) or (II) wherein n is 0, Z is —CH₂—, R₁ is aryloxyalkyl,and R₃ is R₄—C(O)—R₅— wherein R₄ is (R₁₁)(R₁₂)N— as defined therein andR₅ is alkylene.

Another most highly preferred embodiment of the invention is a compoundof formula (I) or (II) wherein n is 0, Z is —CH₂—, R₁ is arylalkyl, andR₃ is R₄—C(O)—R₅— wherein R₄ is (R₁₁)(R₁₂)N— as defined therein and R₅is alkylene.

Another most highly preferred embodiment of the invention is a compoundof formula (I) or (II) wherein n is 0, Z is —CH₂—, R₁ is aryl, and R₃ isR₄—C(O)—R₅— wherein R₄ is (R₁₁)(R₁₂)N— as defined therein and R₅ isalkylene.

Another most highly preferred embodiment of the invention is a compoundof formula (I) or (II) wherein n is 0, Z is —CH₂—, R₁ is(N-alkanoyl-N-alkyl)aminoalkyl, and R₃ is R₄—C(O)—R₅— wherein R₄ is(R₁₁)(R₁₂)N— as defined therein and R₅ is alkylene.

Another most highly preferred embodiment of the invention is a compoundof formula (I) or (II) wherein n is 0, Z is —CH₂—, R₁ isalkylsulfonylamidoalkyl, and R₃ is R₄—C(O)—R₅— wherein R₄ is(R₁₁)(R₁₂)N— as defined therein and R₅ is alkylene.

The present invention also relates to processes for preparing thecompounds of formula (I) and (II) and to the synthetic intermediatesemployed in these processes.

The present invention also relates to a method of antagonizingendothelin in a mammal (preferably, a human) in need of such treatment,comprising administering to the mammal a therapeutically effectiveamount of a compound of formula (I) or (II).

The invention further relates to endothelin antagonizing compositionscomprising a pharmaceutical carrier and a therapeutically effectiveamount of a compound of formula (I) or (II).

The compounds of the invention comprise two or more asymmetricallysubstituted carbon atoms. As a result, racemic mixtures, mixtures ofdiastereomers, as well as single diastereomers of the compounds of theinvention are included in the present invention. The terms “S” and “R”configuration are as defined by the IUPAC 1974 Recommendations forSection E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45,13-30.

The term “carboxy protecting group” as used herein refers to acarboxylic acid protecting ester group employed lo block or protect thecarboxylic acid functionality while the reactions involving otherfunctional sites of the compound are carried out. Carboxy protectinggroups are disclosed in Greene, “Protective Groups in Organic Synthesis”pp. 152-186 (1981), which is hereby incorporated herein by reference. Inaddition, a carboxy protecting group can be used as a prodrug wherebythe carboxy protecting group can be readily cleaved in vivo , forexample by enzymatic hydrolysis, to release the biologically activeparent. T. Higuchi and V. Stella provide a thorough discussion of theprodrug concept in “Pro-drugs as Novel Delivery Systems”, Vol 14 of theA.C.S. Symposium Series, American Chemical Society (1975), which ishereby incorporated herein by reference. Such carboxy protecting groupsare well known to those skilled in the art, having been extensively usedin the protection of carboxyl groups in the penicillin and cephalosporinfields, as described in U.S. Pat. Nos. 3,840,556 and 3,719,667, thedisclosures of which are hereby incorporated herein by reference.Examples of esters useful as prodrugs for compounds containing carboxylgroups can be found on pages 14-21 of “Bioreversible Carriers in DrugDesign: Theory and Application”, edited by E. B. Roche, Pergamon Press,New York (1987), which is hereby incorporated herein by reference.Representative carboxy protecting groups are C₁ to C₈ alkyl (e.g.,methyl, ethyl or tertiary butyl and the like); haloalkyl; alkenyl;cycloalkyl and substituted derivatives thereof such as cyclohexyl,cylcopentyl and the like; cycloalkylalkyl and substituted derivativesthereof such as cyclohexylmethyl, cylcopentylmethyl and the like;arylalkyl, for example, phenethyl or benzyl and substituted derivativesthereof such as alkoxybenzyl or nitrobenzyl groups and the like;arylalkenyl, for example, phenylethenyl and the like; aryl andsubstituted derivatives thereof, for example, 5-indanyl and the like;dialkylaminoalkyl (e.g., dimethylaminoethyl and the like);alkanoyloxyalkyl groups such as acetoxymethyl, butyryloxymethyl,valeryloxymethyl, isobutyryloxymethyl, isovaleryloxymethyl,1-(propionyloxy)-1-ethyl, 1-(pivaloyloxyl)-1-ethyl,1-methyl-1-(propionyloxy)-1-ethyl, pivaloyloxymethyl, propionyloxymethyland the like; cycloalkanoyloxyalkyl groups such ascyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl,cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl and the like;aroyloxyalkyl, such as benzoyloxymethyl, benzoyloxyethyl and the like;arylalkylcarbonyloxyalkyl, such as benzylcarbonyloxymethyl,2-benzylcarbonyloxyethyl and the like; alkoxycarbonylalkyl, such asmethoxycarbonylmethyl, cyclohexyloxycarbonylmethyl,1-methoxycarbonyl-1-ethyl, and the like; alkoxycarbonyloxyalkyl, such asmethoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl,1-ethoxycarbonyloxy-1-ethyl, 1-cyclohexyloxycarbonyloxy-1-ethyl and thelike; alkoxycarbonylaminoalkyl, such as t-butyloxycarbonylaminomethyland the like; alkylaminocarbonylaminoalkyl, such asmethylaminocarbonylaminomethyl and the like; alkanoylaminoalkyl, such asacetylaminomethyl and the like; heterocycliccarbonyloxyalkyl, such as4-methylpiperazinylcarbonyloxymethyl and the like;dialkylaminocarbonylalkyl, such as dimethylaminocarbonylmethyl,diethylaminocarbonylmethyl and the like;(5-(loweralkyl)-2-oxo-1,3-dioxolen-4-yl)alkyl, such as(5-t-butyl-2-oxo-1,3-dioxolen-4-yl)methyl and the like; and(5-phenyl-2-oxo-1,3-dioxolen-4-yl)alkyl, such as(5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl and the like.

The term “N-protecting group” or “N-protected” as used herein refers tothose groups intended to protect the N-terminus of an amino acid orpeptide or to protect an amino group against undersirable reactionsduring synthetic procedures. Commonly used N-protecting groups aredisclosed in Greene, “Protective Groups In Organic Synthesis,” (JohnWiley & Sons, New York (1981)), which is hereby incorporated byreference. N-protecting groups comprise acyl groups such as formyl,acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl,2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl,o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl,4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such asbenzenesulfonyl, p-toluenesulfonyl and the like; carbamate forminggroups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl,t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl,fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and thelike; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl andthe like; and silyl groups such as trimethylsilyl and the like.Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl,t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) andbenzyloxycarbonyl (Cbz).

The term “alkanoyl” as used herein refers to an alkyl group aspreviously defined appended to the parent molecular moiety through acarbonyl (—C(O)—) group. Examples of alkanoyl include acetyl, propionyland the like.

The term “alkanoylamino” as used herein refers to an alkanoyl group aspreviously defined appended to an amino group. Examples alkanoylaminoinclude acetamido, propionylamido and the like.

The term “alkanoylaminoalkyl” as used herein refers to R₄₃—NH—R₄₄—wherein R₄₃ is an alkanoyl group and R₄₄ is an alkylene group.

The term “alkanoyloxyalkyl” as used herein refers to R₃₀—O—R₃₁— whereinR₃₀ is an alkanoyl group and R₃₁ is an alkylene group. Examples ofalkanoyloxyalkyl include acetoxymethyl, acetoxyethyl and the like.

The term “alkenyl” as used herein refers to a straight or branched chainhydrocarbon radical containing from 2 to 15 carbon atoms and alsocontaining at least one carbon-carbon double bond. Alkenyl groupsinclude, for example, vinyl (ethenyl), allyl (propenyl), butenyl,1-methyl-2-buten-1-yl and the like.

The term “alkenylene” denotes a divalent group derived from a straightor branched chain hydrocarbon containing from 2 to 15 carbon atoms andalso containing at least one carbon—carbon double bond. Examples ofalkenylene include —CH═CH—, —CH₂CH═CH—, —C(CH₃)═CH—, —CH₂CH═CHCH₂—, andthe like.

The term “alkenyloxy” as used herein refers to an alkenyl group, aspreviously defined, connected to the parent molecular moiety through anoxygen (—O—) linkage. Examples of alkenyloxy include allyloxy,butenyloxy and the like.

The term “alkoxy” as used herein refers to R₄₁O— wherein R₄₁ is aloweralkyl group, as defined herein. Examples of alkoxy include, but arenot limited to, ethoxy, tert-butoxy, and the like.

The term “alkoxyalkoxy” as used herein refers to R₈₀O—R₈₁O— wherein R₈₀is loweralkyl as defined above and R₈₁ is alkylene. Representativeexamples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy,t-butoxymethoxy and the like.

The term “alkoxyalkoxyalkyl” as used herein refers to an alkoxyalkoxygroup as previously defined appended to an alkyl radical. Representativeexamples of alkoxyalkoxyalkyl groups include methoxyethoxyethyl,methoxymethoxymethyl, and the like.

The term “alkoxyalkyl” as used herein refers to an alkoxy group aspreviously defined appended to an alkyl radical as previously defined.Examples of alkoxyalkyl include, but are not limited to, methoxymethyl,methoxyethyl, isopropoxymethyl and the like.

The term “alkoxycarbonyl” as used herein refers to an alkoxyl group aspreviously defined appended to the parent molecular moiety through acarbonyl group. Examples of alkoxycarbonyl include methoxycarbonyl,ethoxycarbonyl, isopropoxycarbonyl and the like.

The term “alkoxyarbonylalkenyl” as used herein refers to analkoxycarbonyl group as previously defined appended to an alkenylradical. Examples of alkoxycarbonylalkenyl includemethoxycarbonylethenyl, ethoxycarbonylethenyl and the like.

The term “alkoxycarbonylalkyl” as used herein refers to R₃₄—C(O)—R₃₅—wherein R₃₄ is an alkoxy group and R₃₅ is an alkylene group. Examples ofalkoxycarbonylalkyl include methoxycarbonylmethyl, methoxcarbonylethyl,ethoxycarbonylmethyl and the like.

The term “alkoxycarbonylaminoalkyl” as used herein refers toR₃₈—C(O)—NH—R₃₉— wherein R₃₈ is an alkoxy group and R₃₉ is an alkylenegroup.

The term “alkoxycarbonyloxyalkyl” as used herein refers toR₃₆—C(O)—O—R₃₇— wherein R₃₆ is an alkoxy group and R₃₇ is an alkylenegroup.

The term “(alkoxycarbonyl)thioalkoxy” as used herein refers to analkoxycarbonyl group as previously defined appended to a thioalkoxyradical. Examples of (alkoxycarbonyl)thioalkoxy includemethoxycarbonylthiomethoxy, ethoxycarbonylthiomethoxy and the like.

The term “alkoxyhaloalkyl” as used herein refers to a haloalkyl radicalto which is appended an alkoxy group.

The terms “alkyl” and “loweralkyl” as used herein refer to straight orbranched chain alkyl radicals containing from 1 to 15 carbon atomsincluding, but not limited to, methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl,2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and thelike.

The term “(N-alkanoyl-N-alkyl)aminoalkyl” as used herein refers toR₈₅C(O)N(R₈₆)R₈₇— wherein R₈₅ is an alkanoyl as previously defined, R₈₆is loweralkyl, and R₈₇ is alkylene.

The term “alkylamino” as used herein refers to R₅₁NH— wherein R₅₁ is aloweralkyl group, for example, ethylamino, butylamino, and the like.

The term “alkylaminoalkyl” as used herein refers to a loweralkyl radicalto which is appended an alkylamino group.

The term “alkylaminocarbonyl” as used herein refers to an alkylaminogroup, as previously defined, appended to the parent molecular moietythrough a carbonyl (—C(O)—) linkage. Examples of alkylaminocarbonylinclude methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyland the like.

The term “alkylaminocarbonylalkenyl” as used herein refers to an alkenylradical to which is appended an alkylaminocarbonyl group.

The term “alkylaminocarbonylalkyl” as used herein refers to a loweralkylradical to which is appended an alkylaminocarbonyl group.

The term “alkylaminocarbonylaminoalkyl” as used herein refers toR₄₀—C(O)—NH—R₄₁— wherein R₄₀ is an alkylamino group and R₄₁ is analkylene group.

The term “alkylene” denotes a divalent group derived from a straight orbranched chain saturated hydrocarbon having from 1 to 15 carbon atoms bythe removal of two hydrogen atoms, for example —CH₂—, —CH₂CH₂—,—CH(CH₃)—, —CH₂CH₂CH₂—, —CH₂C(CH₃)₂CH₂— and the like.

The term “alkylsulfonylamidoalkyl” as used herein refers R₈₈S(O)₂NHR₈₉—wherein R₈₈ is loweralkyl and R₈₉ is alkylene.

The term “alkylsulfonylamino” as used herein refers to an alkyl group aspreviously defined appended to the parent molecular moiety through asulfonylamino (—S(O)₂—NH—) group. Examples of alkylsulfonylamino includemethylsulfonylamino, ethylsulfonylamino, isopropylsulfonylamino and thelike.

The term “alkynyl” as used herein refers to a straight or branched chainhydrocarbon radical containing from 2 to 15 carbon atoms and alsocontaining at least one carbon—carbon triple bond. Examples of alkynylinclude —C≡C—H, H—C≡C—CH₂—, H—C≡C—CH(CH₃)— and the like.

The term “alkynylene” refers to a divalent group derived by the removalof two hydrogen atoms from a straight or branched chain acyclichydrocarbon group containing from 2 to 15 carbon atoms and alsocontaining a carbon-carbon triple bond. Examples of alkynylene include—C≡C—, —C≡C—CH₂—, —C≡C—CH(CH₃)— and the like.

The term “aminoalkyl” as used herein refers to a —NH₂, alkylamino, ordialkylamino group appended to the parent molecular moiety through analkylene.

The term “aminocarbonyl” as used herein refers to H₂N—C(O)—.

The term “aminocarbonylalkenyl” as used herein refers to an alkenylradical to which is appended an aminocarbonyl (NH₂C(O)—) group.

The term “aminocarbonylalkoxy” as used herein refers to H₂N—C(O)—appended to an alkoxy group as previously defined. Examples ofaminocarbonylalkoxy include aminocarbonylmethoxy, aminocarbonylethoxyand the like.

The term “aminocarbonylalkyl” as used herein refers to a loweralkylradical to which is appended an aminocarbonyl (NH₂C(O)—) group.

The term “trialkylaminoalkyl” as used herein refers to(R₉₀)(R₉₁)(R₉₂)N(R₉₃)— wherein R₉₀, R₉₁, and R₉₂ are independentlyselected from loweralkyl and R₉₃ is alkylene.

The term “aroyloxyalkyl” as used herein refers to R₃₂—C(O)—O—R₃₃—wherein R₃₂ is an aryl group and R₃₃ is an alkylene group. Examples ofaroyloxyalkyl include benzoyloxymethyl, benzoyloxyethyl and the like.

The term “aryl” as used herein refers to a mono- or bicyclic carbocyclicring system having one or two aromatic rings including, but not limitedto, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.Aryl groups can be unsubstituted or substituted with one, two or threesubstituents independently selected from loweralkyl, halo, haloalkyl,haloalkoxy, hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy,alkoxycarbonyl, alkoxycarbonylalkenyl, (alkoxycarbonyl)thioalkoxy,thioalkoxy, amino, alkylamino, dialkylamino, aminoalkyl,trialkylaminoalkyl, aminocarbonyl, aminocarbonylalkoxy, alkanoylamino,arylalkoxy, aryloxy, mercapto, cyano, nitro, carboxaldehyde, carboxy,carboxyalkenyl, carboxyalkoxy, alkylsulfonylamino, cyanoalkoxy,(heterocyclic)alkoxy, hydroxy, hydroxalkoxy, phenyl andtetrazolylalkoxy. In addition, substituted aryl groups includetetrafluorophenyl and pentafluorophenyl.

The term “arylalkenyl” as used herein refers to an alkenyl radical towhich is appended an aryl group, for example, phenylethenyl and thelike.

The term “arylalkoxy” as used herein refers to R₄₂O— wherein R₄₂ is anarylalkyl group, for example, benzyloxy, and the like.

The term “arylalkoxyalkyl” as used herein refers to a loweralkyl radicalto which is appended an arylalkoxy group, for example, benzyloxymethyland the like.

The term “arylalkyl” as used herein refers to an aryl group aspreviously defined, appended to a loweralkyl radical, for example,benzyl and the like.

The term “aryloxy” as used herein refers to R₄₅O— wherein R₄₅ is an arylgroup, for example, phenoxy, and the like.

The term “arylalkylcarbonyloxyalkyl” as used herein refers to aloweralkyl radical to which is appended an arylalkylcarbonyloxy group(i.e., R₆₂C(O)O— wherein R₆₂ is an arylalkyl group).

The term “aryloxyalkyl” refers to an aryloxy group as previously definedappended to an alkyl radical. Examples of aryloxyalkyl includephenoxymethyl, 2-phenoxyethyl and the like.

The term “carboxaldehyde” as used herein refers to a formaldehyderadical, —C(O)H.

The term “carboxy” as used herein refers to a carboxylic acid radical,—C(O)OH.

The term “carboxyalkenyl” as used herein refers to a carboxy group aspreviously defined appended to an alkenyl radical as previously defined.Examples of carboxyalkenyl include 2-carboxyethenyl, 3-carboxy-1-ethenyland the like.

The term “carboxyalkoxy” as used herein refers to a carboxy group aspreviously defined appended to an alkoxy radical as previously defined.Examples of carboxyalkoxy include carboxymethoxy, carboxyethoxy and thelike.

The term “cyanoalkoxy” as used herein refers to an alkoxy radical aspreviously defined to which is appended a cyano (—CN) group. Examples ofcyanoalkoxy include 3-cyanopropoxy, 4-cyanobutoxy and the like.

The term “cycloalkanoyloxyalkyl” as used herein refers to a loweralkylradical to which is appended a cycloalkanoyloxy group (i.e., R₆₀—C(O)—O—wherein R₆₀ is a cycloalkyl group).

The term “cycloalkyl” as used herein refers to an aliphatic ring systemhaving 3 to 10 carbon atoms and 1 to 3 rings including, but not limitedto, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl, and thelike. Cycloalkyl groups can be unsubstituted or substituted with one,two or three substituents independently selected from loweralkyl,haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy,halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl andcarboxamide.

The term “cycloalkylalkyl” as used herein refers to a cycloalkyl groupappended to a loweralkyl radical, including but not limited tocyclohexylmethyl.

The term “dialkylamino” as used herein refers to R₅₆R₅₇N— wherein R₅₆and R₅₇ are independently selected from loweralkyl, for examplediethylamino, methyl propylamino, and the like.

The term “dialkylaminoalkyl” as used herein refers to a loweralkylradical to which is appended a dialkylamino group.

The term “dialkylaminocarbonyl” as used herein refers to a dialkylaminogroup, as previously defined, appended to the parent molecular moietythrough a carbonyl (—C(O)—) linkage. Examples of dialkylaminocarbonylinclude dimethylaminocarbonyl, diethylaminocarbonyl and the like.

The term “dialkylaminocarbonylalkenyl” as used herein refers to analkenyl radical to which is appended a dialkylaminocarbonyl group.

The term “dialkylaminocarbonylalkyl” as used herein refers toR₅₀—C(O)—R₅₁— wherein R₅₀ is a dialkylamino group and R₅₁ is an alkylenegroup.

The term “halo” or “halogen” as used herein refers to I, Br, Cl or F.

The term “haloalkenyl” as used herein refers to an alkenyl radical towhich is appended at least one halogen substituent.

The term “haloalkoxy” as used herein refers to an alkoxy radical asdefined above, bearing at least one halogen substituent, for example,2-fluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethoxy,2,2,3,3,3-pentafluoropropoxy and the like.

The term “haloalkoxyalkyl” as used herein refers to a loweralkyl radicalto which is appended a haloalkoxy group.

The term “haloalkyl” as used herein refers to a lower alkyl radical, asdefined above, to which is appended at least one halogen substituent,for example, chloromethyl, fluoroethyl, trifluoromethyl orpentafluoroethyl and the like.

The term “heterocyclic ring” or “heterocyclic” or “heterocycle” as usedherein refers to any 3- or 4-membered ring containing a heteroatomselected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-memberedring containing one, two or three nitrogen atoms; one oxygen atom; onesulfur atom; one nitrogen and one sulfur atom; one nitrogen and oneoxygen atom; two oxygen atoms in non-adjacent positions; one oxygen andone sulfur atom in non-adjacent positions; or two sulfur atoms innon-adjacent positions. The 5-membered ring has 0-2 double bonds and the6- and 7-membered rings have 0-3 double bonds. The nitrogen heteroatomscan be optionally quaternized. The term “heterocyclic” also includesbicyclic groups in which any of the above heterocyclic rings is fused toa benzene ring or a cyclohexane ring or another heterocyclic ring (forexample, indolyl, dihydroindolyl, quinolyl, isoquinolyl,tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl,decahydroisoquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl andthe like). Heterocyclics include: aziridinyl, azetidinyl, pyrrolyl,pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl,homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl,oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl,thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl,isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl,benzothiazolyl, benzoxazolyl, oxetanyl, furyl, tetrahydrofuranyl,thienyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl,oxadiazolyl, thiadiazolyl, pyrrolyl, pyrimidyl and benzothienyl.

Heterocyclics also include compounds of the formula

where X* is —CH₂— or —O— and Y* is —C(O)— or [—C(R″)₂—]_(v) where R″ ishydrogen or C₁-C₄-alkyl and v is 1, 2 or 3 such as 1,3-benzodioxolyl,1,4-benzodioxanyl and the like. Heterocyclics also include bicyclicrings such as quinuclidinyl and the like.

Heterocyclics can be unsubstituted or monosubstituted or disubstitutedwith substituents independently selected from hydroxy, halo, oxo (═O),alkylimino (R*N=wherein R* is a loweralkyl group), amino, alkylamino,dialkylamino, alkoxy, alkoxyalkoxy, aminoalkyl, trialkylaminoalkyl,haloalkyl, cycloalkyl, aryl, arylalkyl, —COOH, —SO₃H, alkoxycarbonyl,nitro, cyano and loweralkyl. In addition, nitrogen containingheterocycles can be N-protected.

The term “(heterocyclic)alkoxy” as used herein refers to a heterocyclicgroup as defined above appended to an alkoxy radical as defined above.Examples of (heterocyclic)alkoxy include 4-pyridylmethoxy,2-pyridylmethoxy and the like.

The term “(heterocyclic)alkyl” as used herein refers to a heterocyclicgroup as defined above appended to a loweralkyl radical as definedabove.

The term “heterocycliccarbonyloxyalkyl” as used herein refers toR₄₆—C(O)—O—R₄₇— wherein R₄₆ is a heterocyclic group and R₄₇ is analkylene group.

The term “hydroxy” as used herein refers to —OH.

The term “hydroxyalkenyl” as used herein refers to an alkenyl radical towhich is appended a hydroxy group.

The term “hydroxyalkoxy” as used herein refers to an alkoxy radical aspreviously defined to which is appended a hydroxy (—OH) group. Examplesof hydroxyalkoxy include 3-hydroxypropoxy, 4-hydroxybutoxy and the like.

The term “hydroxyalkyl” as used herein refers to a loweralkyl radical towhich is appended a hydroxy group.

The term “leaving group” as used herein refers to a halide (for example,Cl, Br or I) or a sulfonate (for example, mesylate, tosylate, triflateand the like).

The term “mercapto” as used herein refers to —SH.

The terms “methylenedioxy” and “ethylenedioxy” refer to one or twocarbon chains attached to the parent molecular moiety through two oxygenatoms. In the case of methylenedioxy, a fused 5 membered ring is formed.In the case of ethylenedioxy, a fused 6 membered ring is formed.Methylenedixoy substituted on a phenyl ring results in the formation ofa benzodioxolyl radical.

Ethylenedioxy substituted on a phenyl ring results in the formation of abenzodioxanyl radical

The term “substantially pure” as used herein means 95% or more of thespecified compound.

The term “tetrazolyl” as used herein refers to a radical of the formula

or a tautomer thereof.

The term “tetrazolylalkoxy” as used herein refers to a tetrazolylradical as defined above appended to an alkoxy group as defined above.Examples of tetrazolylalkoxy include tetrazolylmethoxy, tetrazolylethoxyand the like.

The term “thioalkoxy” as used herein refers to R₇₀S— wherein R₇₀ isloweralkyl. Examples of thioalkoxy include, but are not limited to,methylthio, ethylthio and the like.

The term “thioalkoxyalkoxy” as used herein refers to R₈₀S—R₈₁O— whereinR₈₀ is loweralkyl as defined above and R₈₁ is alkylene. Representativeexamples of alkoxyalkoxy groups include CH₃SCH₂O—, EtSCH₂O—, t-BuSCH₂O—and the like.

The term “thioalkoxyalkoxyalkyl” as used herein refers to athioalkoxyalkoxy group appended to an alkyl radical. Representativeexamples of alkoxyalkoxyalkyl groups include CH₃SCH₂CH₂OCH₂CH₂—,CH₃SCH₂OCH₂—, and the like.

The term “trans,trans” as used herein refers to the orientation ofsubstituents (R₁ and R₂) relative to the central substituent R as shown

The term “trans,cis” as used herein refers to the orientation ofsubstituents (R₁ and R₂) relative to the central substituent R as shown

This definition encompasses both the case where R and R₂ are cis and Rand R₁ are trans and the case where R₂ and R are trans and R and R₁ arecis.

The term “cis,cis” as used herein refers to the orientation ofsubstituents (R₁ and R₂) relative to the central substituent R as shown

Preferred compounds of the invention are selected from the groupconsisting of:

trans-trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[3-(N-propyl-N-n-pentanesulfonylamino)propyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(4-Methoxymethoxyphenyl)-4-(1,3-benzodioxol-5-yl)-(2-(N-propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3-carboxylicacid;

trans,trans-2-(3,4-Dimethoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3-carboxylicacid;

trans,trans-2-(3,4-Dimethoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-n-hexanesulfonylamino)ethyl]pyrrolidine-3-carboxylicacid;

trans,trans-2-(4-Propoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3-carboxylicacid;

trans,trans-2-(3,4-Difluorophenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(3,4-Difluorophenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3-carboxylicacid;

trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-n-hexanesulfonylamino)ethyl]pyrrolidine-3-carboxylicacid;

trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-propyl-N-(3-chloropropanesulfonyl)amino)ethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-isobutyl-N-(3-chloropropanesulfonyl)amino)ethyl)pyrrolidine-3-carboxylicacid;

trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-(4-methylbutanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylicacid;

trans,trans-2-(4-Methoxy-3-fluorophenyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-(n-pentanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylicacid;

trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-(2,2,3,3,3-pentafluoropropoxyethanesulfonyl)-amino)ethyl]pyrrolidine-3-carboxylicacid;

trans,trans-2-(1,4-Benzodioxan-6-yl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-(n-pentanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylicacid;

trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-isobutyl-N-(pentanesulfonylamino)ethyl)pyrrolidine-3-carboxylicacid;

trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-(2-methoxyethyl)-N-(3-chloropropanesulfonyl)amino)-ethyl)pyrrolidine-3-carboxylicacid;

trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-(2-methoxyethyl)-N-(pentanesulfonyl)amino)ethyl)pyrrolidine-3-carboxylicacid;

trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-((2,2,2-trifluoroethoxyethane)sulfonyl)amino)-ethyl]pyrrolidine-3-carboxylicacid;

trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-(2-methoxyethyl)-N-(butanesulfonylamino)ethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-(2-methylpropanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylicacid;

trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-isobutyl-N-(butanesulfonylamino))ethyl)pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-Methylpentyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2,2-Dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1,3-Dioxo-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Tetrahydro-2H-pyran)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2,2,4-Trimethyl-3-pentenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2,2,-Dimethyl-2-(1,3-dioxolan-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1,3-Dioxo-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[[N-4-heptyl-N(2methyl-3-fluorophenyl)]amino carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylicacid;

trans,trans-2-((2-Methoxyphenoxy)-methyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

(2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2,2-dimethylpentyl)-4-(2,3-dihydro-benzofuran-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2,2,-Dimethyl-2-(1,3-dioxolan-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2,2-Dimethyl-3-(E)-pentenyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-pyridyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

(2S, 3R,4S)-2-(2-(2-oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

(2S, 3R,4S)-2-(2-(2-oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1-pyrazolyl)ethyl)-4-(1,3-benzodioxol-5-y)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

(2R,3R,4S)-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)1-(2-(N-propyl-N-pentanesulfonylamino)ethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2,2-Dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-1-((N-butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-((N-butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2,2-Dimethylpent-3-enyl)-4-(1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2,2-Dimethylpent-3-enyl)-4-(1,3-benzodioxol-5-yl)-1-((N-butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-((N-butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2,2,4-Trimethylpent-3-enyl)-4-(1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2,2,4-Trimethylpent-3-enyl)-4-(1,3-benzodioxol-5-yl)-1-((N-butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2,2,4-Trimethylpent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2,2,4-Trimethylpent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2,2,4-Trimethylpent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-((N-butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1,3-Dioxol-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2,2,-Dimethyl-2-(1,3-Dioxol-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2,2-Dimethyl-2-(1,3-dioxolan-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2,2,-Dimethyl-2-(1,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2,2-Dimethyl-2-(1,3-dioxolan-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))amino)carbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-((2-Methoxyphenoxy)-methyl)-4-(1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-((2-Methoxyphenoxy)-methyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-((2-Methoxyphenoxy)-methyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-((2-Methoxyphenoxy)-methyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Methoxyphenoxy)-methyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Oxo 1,2-dihydropyridin-1-yl)-ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Oxopyridin-1-yl)-ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Oxopyridin-1-yl)-ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Oxopyridin-1-yl)-ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Oxopyridin-1-yl)-ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Oxopyridin-1-yl)-ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-((N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2(-2-Oxopiperidin-1-yl)-ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Oxopiperidin-1-yl)-ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Oxopiperidin-1-yl)-ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Oxopiperidin-1-yl)-ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Oxopiperidin-1-yl)-ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Oxopiperidin-1-yl)-ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;

trans,trans-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-trimethylammoniobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-trimethylammoniobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(2,3-dihydro-benzofuran-5-yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(2,3-dihydrobenzofuran-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(2,3-dihydrobenzofuran-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(3,3-Dimethyl-2-oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(3,3-Dimethyl-2-oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(3,3-Dimethyl-2-oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(4,4-Dimethyl-2-oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(4,4-Dimethyl-2-oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(4,4-Dimethyl-2-oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1-propanesultamyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;

trans,trans-2-(2-(1-propanesultamyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1-propanesultamyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1-propanesultamyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(propoxy)amino)carbonylmethyll-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1-propanesultamyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;

trans,trans-2-(2-(1-propanesultamyl)ethyl)-4-(7-methoxy-1,3-berizodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1-propanesultamyl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1-propanesultamyl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1-propanesultamyl)ethyl)-4-(2,3-dihydrobenzofuran-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1-propanesultamyl)ethyl)-4-(2,3-dihydrobenzofuran-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1-propanesultamyl)ethyl)-4-(2,3-dihydrobenzofuran-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1-pyrazolyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1-pyrazolyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1-pyrazolyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N-butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1-pyrazolyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1-pyrazolyl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1-pyrazolyl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1-pyrazolyl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1-pyrazolyl)ethyl)-4-(2,3-dihydro-benzofuran-5-yl)-1-(N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1-pyrazolyl)ethyl)-4-(2,3-dihydro-benzofuran-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1-pyrazolyl)ethyl)-4-(2,3-dihydro-benzofuran-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-oxazolyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(Oxazol-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(Oxazol-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(Oxazol-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(Oxazol-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(Oxazol-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(Oxazol-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(Oxazol-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl-]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(5-Methyloxazol-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(5-Methyloxazol-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-((N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(5-Methyloxazol-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2,5-Dioxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2,5-Dioxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2,5-Dioxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2,5-Dioxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2,5-Dioxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2,5-Dioxopyrrolidin-1-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2,5-Dioxopyrrolidin-1-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(Pyridin-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-((N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl-3-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(Pyridin-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(Pyridin-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(propoxy)amino)carbonylmethyll-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(Pyridin-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(Pyridin-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxo-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(Pyridin-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-l-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(Pyridin-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(Pyrimidin-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(Pyrimidin-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(Pyrimidin-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-((N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1,3-benzodioxol-4-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1,3-benzodioxol-4-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicacid; and

trans,trans-2-(2-(1,3-benzodioxol-4-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;

(2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

(2S,3R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

(2S,3R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

(2S,3R,4S)-2-((2-Methoxyphenoxy)-methyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

(2S,3R,4S)-2-(2-(2-Methoxyphenyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

or a pharmaceutically acceptable salt.

Most preferred compounds of the invention are selected from the groupconsisting of:

trans,trans-2-(2-(1,3-Dioxol-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2,2,-Dimethyl-2-(1,3-dioxolan-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1,3-Dioxol-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[[N-4-heptyl-N-(2-methyl-3-fluorophenyl)]aminocarbonylmethyl]-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-l-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;

trans,trans-2-((2-Methoxyphenoxy)-methyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2,2,-Dimethyl-2-(1,3-dioxolan-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2,2-Dimethyl-3-(E)-pentenyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(2-pyridyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

(2S, 3R,4S)-2-(2-(2-oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

(2S, 3R, 4S)-2-(2,2Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

(2S, 3R,4S)-2-(2-(2-oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

trans,trans-2-(2-(1-pyrazolyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

(2R, 3R,4S)-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[((N-propyl-N-pentanesulfonyl)amino)ethyl]-pyrrolidine-3-carboxylicacid;

(2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

(2S,3R ,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

(2S,3R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

(2S,3R,4S)-2-((2-Methoxyphenoxy)-methyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid; and

(2S,3R,4S)-2-(2-(2-Methoxyphenyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

or a pharmaceutically acceptable salt thereof.

Methods for preparing the compounds of the invention are shown inSchemes I-XV.

Scheme I illustrates the general procedure for preparing the compoundsof the invention when n and m are 0, Z is —CH₂— and W is —CO₂H. Aβ-ketoester 1, where E is loweralkyl or a carboxy protecting group isreacted with a nitro vinyl compound 2, in the presence of a base (forexample, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or sodium ethoxide orsodium hydride and the like) in an inert solvent such as toluene,benzene, tetrahydrofuran or ethanol and the like. The condensationproduct 3 is reduced (for example, hydrogenation using a Raney nickel orplatinum catalyst). The resulting amine cyclizes to give the dihydropyrrole 4. Reduction of 4 (for example, sodium cyanoborohydride orcatalytic hydrogenation and the like) in a protic solvent such asethanol or methanol and the like gives the pyrrolidine compound 5 as amixture of cis-cis, trans,trans and cis,trans products. Chromatographicseparation removes the cis-cis isomer leaving a mixture of thetrans,trans and cis,trans isomers which is further elaborated. Thecis-cis isomer can be epimerized (for example, using sodium ethoxide inethanol) to give the trans,trans isomer and then carried on as describedbelow. The pyrrolidine nitrogen is (1) acylated or sulfonylated withR₃—X (R₃ is R₄—C(O)— or R₆—S(O)₂— and X is a leaving group such as ahalide (Cl is preferred) or X taken together with R₄—C(O)— or R₆—S(O)₂—forms an activated ester including esters or anhydrides derived fromformic acid, acetic acid and the like, alkoxycarbonyl halides,N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxybenzotriazole,N-hydroxy-5-norbornene-2,3-dicarboxamide, 2,4,5-trichlorophenol and thelike) or (2) alkylated with R₃—X where X is a leaving group (forexample, X is a halide (for example, Cl, Br or I) or X is a leavinggroup such as a sulfonate (for example, mesylate, tosylate, triflate andthe like)) in the presence of a base such as diisopropyl ethylamine ortriethylamine and the like to give the N-derivatized pyrrolidine 6 whichis still a mixture of trans,trans and cis,trans isomers. Hydrolysis ofthe ester 6 (for example, using a base such a sodium hydroxide inEtOH/H₂O) selectively hydrolyzes the trans,trans ester to give a mixtureof 7 and 8, which are readily separated.

Scheme II illustrates a general procedure for preparing the compounds ofthe invention when n is 1, m is 0, Z is —CH₂— and W is —CO₂H. Asubstituted benzyl chloride 9 is reacted with a lithio dithiane 10 in aninert solvent such as THF or dimethoxyethane to give the alkylatedadduct 11. The anion of compound 11 is formed using a base such asn-butyllithium and then reacted with R₁—CH₂—X′ wherein X′ is a leavinggroup such as a halide or sulfonate to give compound 12. The dithianeprotecting group is cleaved (for example, using a mercuric salt inwater) to give the keto compound 13. Reaction of ketone 13 with benzylamine and formaldehyde gives the keto piperidine compound 14. Treatmentof compound 14 with an activated nitrile such as trimethylsilyl cyanidefollowed by a dehydrating agent such as phosphorous oxychloride providesthe isomeric ene nitrites 15. Reduction of the double bond (for example,using sodium borohydride) affords the piperidinyl nitrile 16. Hydrolysisof the nitrile using hydrochloric acid in the presence of a carboxyprotecting reagent (for example, an alkyl alcohol) affords ester 17(where E is a carboxy protecting group). Debenzylation by catalytichydrogenation under acidic conditions affords the free piperidinecompound 18. Compound 18 is further elaborated by the proceduresdescribed in Scheme I for compound 5 to give the final product compound19.

Scheme III illustrates a general procedure for preparing the compoundsof the invention when m and n are 0, Z is —C(O)— and W is —CO₂H. β-Ketoester 20 (wherein E is loweralkyl or a carboxy protecting group) isreacted with an α-haloester 21 (where J is lower alkyl or a carboxyprotecting group and the halogen is bromine, iodine or chlorine) in thepresence of a base such as NaH or potassium tert-butoxide or lithiumdiisopropylamide in an inert solvent such as THF or dimethoxyethane togive diester 22. Treating compound 22 with R₃—NH₂ and heating in aceticacid gives the cyclic compound 23. The double bond is reduced (forexample, by catalytic hydrogenation using a palladium on carbon catalystor sodium cyanoborohydride reduction) to give pyrrolidone 24.Epimerization with sodium ethoxide in ethanol to give the desiredtrans,trans configuration, followed by sodium hydroxide hydrolysis ofthe ester, affords the desired trans,trans carboxylic acid 25.

Scheme IV illustrates a general procedure for preparing the compounds ofthe invention when n is 0, m is 1, Z is —CH₂— and W is —CO₂H. Thetrans,trans compound 7, prepared in Scheme I, is homologated by theArndt-Eistert synthesis. The carboxy terminus is activated (for example,by making the acid chloride using thionyl chloride) to give compound 52,where L is a leaving group (in the case of an acid chloride, L is Cl).Compound 52 is treated with diazomethane to give the diato ketone 53.Rearrangement of compound 53 (for example, using water or an alcohol andsilver oxide or silver benzoate and triethylamine, or heating orphotolysis in the presence of water or an alcohol) affords the aceticacid compound 54 or an ester which may be hydrolyzed. Compounds where mis from 2 to 6 can be obtained by repetition of the above describedprocess.

A preferred embodiment is shown in Schemes V and VI. A benzoyl acetate26 is reacted with a nitro vinyl benzodioxolyl compound 27 using1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the base in toluene to givecompound 28. Catalytic hydrogenation using Raney nickel leads toreduction of the nitro group to an amine and subsequent cyclization togive the dihydropyrrole 29. The double bond is reduced with sodiumcyanoborohydride to give the pyrrolidine compound 30 as a mixture ofcis—cis, trans,trans and cis,trans isomers. Chromatography separates outthe cis—cis isomer, leaving a mixture of the trans,trans and cis,transisomers (31).

Scheme VI illustrates the further elaboration of the trans,trans isomer.The mixture (31) of trans,trans and cis,trans pyrrolidines described inScheme IV is reacted with N-propyl bromoacetamide in acetonitrile in thepresence of ethyldiisopropylamine to give the alkylated pyrrolidinecompound 32, still as a mixture of trans,trans and cis,trans isomers.Sodium hydroxide in ethanol-water hydrolyzes the ethyl ester of thetrans,trans compound but leaves the ethyl ester of the cis,transcompound untouched, thus allowing separation of the trans,transcarboxylic acid 33 from the cis,trans ester 34.

Scheme VII illustrates the preparation of a specific piperidinylcompound. Benzodioxotyl methyl chloride 35 is reacted with lithiodithiane 36 to give the alkylated compound 37. Treatment of compound 37with 4-methoxybenzyl chloride in the presence of lithiumdiisopropylamide gives compound 38. Cleavage of the dithiane protectinggroup using a mercuric salt in aqueous solution gives ketone 39.Treatment of 39 with benzylamine and formaldehyde gives the ketopiperidine 40. Treatment of compound 40 with trimethylsilyl cyanidefollowed by phosphorous oxychloride gives the ene nitrile as a mixtureof isomers 41. Sodium borohydride reduction of the double bond gives thepiperidinyl nitrile 42. Hydrochloric acid hydrolysis in the presence ofethanol gives ethyl ester 43. The N-benzyl protecting group is removedby catalytic hydrogenation to give the free piperidine compound 44.Compound 44 is further elaborated by the procedures described in SchemeV for compound 31 resulting in the formation of the N-derivatizedcarboxylic acid 45.

A preferred embodiment of the process shown in Scheme III is shown inScheme VIII. 4-Methoxybenzoylacetate 46 (wherein E is loweralkyl or acarboxy protecting group) is reacted with an benzodioxolyla-bromoacetate 47 (wherein E is lower alkyl or a carboxy protectinggroup) in the presence of NaH in THF to give diester 48. Treatingcompound 48 with ethoxypropylamine and heating in acetic acid gives thecyclic compound 49. The double bond is reduced by catalytichydrogenation using a palladium on carbon catalyst to give pyrrolidone50. Epimerization with sodium ethoxide in ethanol to give the desiredtrans,trans configuration is followed by sodium hydroxide hydrolysis ofthe ester to afford the desired trans,trans carboxylic acid 51.

Scheme IX illustrates the preparation of compounds where n is 0, Z is—CH₂—, and W is other than carboxylic acid. Compound 55, which can beprepared by the procedures described in Scheme IV, is converted (forexample, using peptide coupling condition, e.g. N-methylmorpholine, EDCland HOBt, in the presence of ammonia or other amide forming reactions)to give carboxamide 56. The carboxamide is dehydrated (for example,using phosphorus oxychloride in pyridine) to give nitrile 57. Nitrile 57under standard tetrazole forming conditions (sodium azide andtriethylamine hydrochloride or trimethylsilylazide and tin oxide) isreacted to give tetrazole 58. Alternatively nitrile 57 is reacted withhydroxylamine hydrochloride in the presence of a base (for example,potassium carbonate, sodium carbonate, sodium hydroxide, triethylamine,sodium methoxide or NaH) in a solvent such as DMF, DMSO, ordimethylacetamide to give amidoxime 59. The amidoxime 59 is allowed toreact with a methyl or ethyl chloroformate in a conventional organicsolvent (such as, chloroform, methylene chloride, dioxane, THF,acetonitrile or pyridine) in the presence of a base (for example,triethylamine, pyridine, potassium carbonate and sodium carbonate) togive an O-acyl compound. Heating of the O-acyl amidoxime in an inertsolvent (such as benzene, toluene, xylene, dioxane, THF, dichloroethane,or chloroform and the like) results in cyclization to compound 60.Alternatively reacting the amidoxime 59 with thionyl chloride in aninert solvent (for example, chloroform, dichloromethane, dixoane and THFand the like) affords the oxathiadiazole 61.

Scheme X illustrates the preparation of compounds in which R₃ is anacylmethylene group. A carboxylic acid 62 (where R₄ is as previouslydefined herein) is treated with oxalyl chloride in a solution ofmethylene chloride containing a catalytic amount ofN,N-dimethylformamide to give the acid chloride. Treatment of the acidchloride with excess ethereal diazomethane affords a diazoketone, andthen treatment with anhydrous HCl in dioxane gives the α-chloroketone63. Pyrrolidine ester 5 where E is lower alkyl or a carboxy protectinggroup, prepared in Scheme I, is alkylated with the α-chloroketone 63 toprovide alkylated pyrrolidine 64. Carboxy deprotection (for example,hydrolysis of an alkyl ester using lithium or sodium hydroxide inethanol-water) gives the alkylated pyrrolidine acid 65.

Scheme XI illustrates the preparation of “reverse amides andsulfonamides”. The carboxy protected pyrrolidine 5, prepared in SchemeI, is reacted with a difunctionalized compound X—R₈—X where R₈ isalkylene and X is a leaving group (for example a halide where Br ispreferred) to give N-alkylated compound 66. Treatment of 66 with anamine (R₂₀NH₂) affords secondary amine 67. This amine (67) can bereacted with an activated acyl compound (for example, R₄—C(O)—Cl) andthen carboxy deprotected (for example, hydrolysis of an ester orhydrogenation of a benzyl moiety) to afford amide 68. Alternativelyamine 67 can be reacted with an activated sulfonyl compound (forexample, R₆—S(O)₂—Cl) and then carboxy deprotected (for example,hydrolysis of an ester or hydrogenation of a benzyl moiety) to affordsulfonamide 69.

Scheme XII illustrates a method for synthesizing pyrrolidines by anazomethine ylide type [3+2]-cycloaddition to an acrylate. Generalstructures such as compound 70 are known to add to unsaturated esterssuch as 71 to provide pyrrolidines such as compound 72 (O. Tsuge, S.Kanemasa, K. Matsuda, Chem. Lett. 1131-4 (1983), O. Tsuge, S. Kanemasa,T. Yamada, K. Matsuda, J. Org. Chem. 52 2523-30 (1987), and S. Kanemasa,K. Skamoto, O. Tsuge, Bull. Chem. Soc. Jpn. 62 1960-68 (1989)). Aspecific example is also shown in Scheme XII. Silylimine 73 is reactedwith acrylate 74 in the presence of trimethylsilyl triflate andtetrabutylammonium fluoride to give the desired pyrrolidine 75 as amixture of isomers. This method can be modified to provide theN-acetamido derivatives directly by reacting 73 and74 with theappropriate bromoacetamide (for example, dibutyl bromoacetamide) in thepresence of tetrabutylammonium iodide and cesium fluoride to givecompound 76.

Scheme XIII illustrates a method for producing an enantiomerically purepyrrolidine 80, which can be further elaborated on the pyrrolidinenitrogen. Intermediate racemic pyrrolidine ester 77 (for example,prepared by the procedure described in Scheme V) is Boc-nitrogenprotected (for example, by treatment with Boc₂O) and then the ester ishydrolyzed (for example, using sodium or lithium hydroxide in ethanoland water) to give t-butyl carbamoyl pyrrolidine carboxylic acid 78. Thecarboxylic acid is converted to its (+)-cinchonine salt, which can berecrystallized (for example from ethyl acetate and hexane or chloroformand hexane) to afford the diastereomerically pure salt. Thisdiastereomerically pure salt can be neutralized (for example, withsodium carbonate or citric acid) to afford enantiomerically purecarboxylic acid 79. The pyrrolidine nitrogen can be deprotected (forexample, using trifluoroacetic acid) and the ester reformed by the useof ethanolic hydrochloric acid to give salt 80. Alternatively one canuse ethanol HCl to cleave the protecting group and form the ester in onestep. The pyrrolidine nitrogen can be further elaborated (for example,by treatment with the dibutyl amide of bromoacetamide in acetonitrile inthe presence of diisopropylethylamine) to give optically active compound81. The use of (−)-cinchonine will give the opposite enantiomer.

Scheme XIV describes another procedure for preparation of pyrrolidines.Pyrrolidines may be synthesized by the use of an azomethine ylidecycloaddition to an acrylate derivative as described by Cottrell, I. F.,et.al., J. Chem. Soc., Perkin Trans. 1, 5: 1091-97 (1991). Thus, theazomethine ylide precursor 82 (where R₅₅ is hydrogen or methyl) iscondensed with a substituted acrylate 83 (wherein R₂ is as describedherein and R₅₆ is loweralkyl) under acidic conditions to afford thesubstituted pyrrolidine 84. The N-protecting group can be removed (forexample, by hydrogenolysis of an N-benzyl group) to give 85, which canbe alkylated under the conditions described above to provide theN-substituted pyrrolidine 86. Standard ester hydrolysis of 86 producesthe desired pyrrolidine carboxylic acid 87.

A preferred process is shown in Scheme XV. Nitro vinyl compound (88) isreacted with beta-keto ester 89 in the presence of a base such as sodiumethoxide and the like or a trialkylamine such as triethylamine ordiisopropylethylamine and the like or an amidine such as DBU and thelike in an inert solvent such as THF, toluene, DMF, acetonitrile, ethylacetate, isopropyl acetate or methylene chloride and the like at atemperature of from about 0° C. to about 100° C. for a period of timefrom about 15 minutes to overnight to give compound 90. Reduction of thenitro group followed by cyclization was effected for example bycatalytic hydrogenation with a hydrogen pressure of from aboutatmospheric pressure to 300 p.s.i. over from about 1 hour to about 1 dayof compound 90 in an inert solvent such as THF, ethyl acetate, toluene,ethanol, isopropanol, DMF or acetonitrile and the like, using ahydrogenation catalyst such as Raney nickel, palladium on carbon, aplatinum catalyst, such as platinum oxide, platinum on carbon orplatinum on alumina and the like, or a rhodium catalyst, such as rhodiumcarbon or rhodium on alumina and the like, and the like affordsintermediate nitrone 91a or a mixture of nitrone 91a and imine 91b. Thereaction mixture comprising the nitrone or nitrone/imine mixture istreated with an acid such as trifluoroacetic acid or acetic acid orsulfuric acid or phosphoric acid or methanesulfonic acid and the like,and the hydrogenation is continued to give pyrrolidine compound 92 asthe cis,cis-isomer. Epimerization at C-3 is effected by treatment ofcompound 92 with a base such as sodium ethoxide, potassium t-butoxide,lithium t-butoxide or potassium t-amyloxide and the like or atrialkylamine such as triethylamine or diisopropylethylamine and thelike or an amidine such as DBU and the like in an inert solvent such asethanol, ethyl acetate, isopropyl acetate, THF, toluene or DMF and thelike at a temperature of from about −20° C. to about 120° C. to give thetrans,trans compound 93. Compound 93 itself can optionally be resolvedinto enantiomers prior to reacting with X—R₃. The substantially pure(i.e., at least 95% of the desired isomer) optically active (+)-isomerof compound 93 is obtained by treatment of a mixture of the (+)-isomerand the (−)-isomer of 93 with S-(+)-mandelic acid, D-tartaric acid orD-dibenzoyl tartaric acid and the like in a solvent such asacetonitrile, ethyl acetate, isopropyl acetate, ethanol or isopropanoland the like. The (+)-isomer of 93 selectively crystallizes as the salt,leaving the (−)-isomer of 93 in solution. Alternatively, thesubstantially pure (i.e., at least 95% of the desired isomer) opticallyactive (−)-isomer of compound 93 can be selectively crystallized byreaction of a mixture of the (+)-isomer and the (−)-isomer of 93 withL-tartaric acid, L-dibenzoyl tartaric acid or L-pyroglutamic acid andthe like, leaving the desired (+)-isomer of compound 93 in solution.

Compound93 (racemic or optically active) is reacted with X—R₃ (where Xis a leaving group (for example, a halide or a sulfonate) and R₃ is aspreviously defined) using a base such as diisopropylethylamine,triethylamine, sodium bicarbonate or potassium carbonate and the like inan inert solvent such as acetonitrile, THF, toluene, DMF or ethanol andthe like at a temperature of from about 0° C. to about 100° C. to givethe intermediate ester 94. The ester can be isolated or converted insitu to the carboxylic acid (95) using hydrolysis conditions such as abase such as sodium hydroxide or lithium hydroxide or potassiumhydroxide and the like in a solvent such as ethanol-water or THF-ethanoland the like.

A more detailed description of the preparation of some specific analogsis provided in Schemes XVI-XXI. Aliphatic β-ketoesters (Scheme XVI) maybe prepared by copper-catalyzed addition of a Grignard reagent (forexample, propylmagnesium bromide) to an unsaturated ester, for example,ethyl 3,3-dimethylacrylate. The resultant ester is hydrolyzed, forexample with sodium hydroxide in aqueous alcohol, and is homologated instepwise fashion to the corresponding β-ketoester, for example byactivation using carbonyldiimidazole and condensation withmagnesio-ethoxymalonate. Alternatively, olefinic β-ketoesters may beprepared by Claisen rearangement of the corresponding allylic alcohols;hydrolysis and homologation as described above produce the desiredβ-ketoester.

N-alkyl,O-alkyl bromohydroxamates are prepared according to Scheme XVII.N-Boc-O-allyl hydroxylamine is alkylated with and alkyl halide, forexample using sodium hydride as base; the double bond is selectivelyreduced, for example using hydrogen and a palladium catalyst. Afterremoval of the Boc protecting group, for example with TFA, the resultantamine is acylated, for example using bromoacetyl bromide.

The β-ketoesters described in Scheme XVI may be converted to pyrrolidinederivatives as described in Scheme XVIII. Michael addition onto anitrostyrene derivative can be catalyzed with base, for example DBU orpotassium t-butoxide; the resultant adduct is hydrogenated, for exampleusing Raney Nickel as catalyst, to give an imine, which is reducedfurther, for example using sodium cyanoborohydride under controlled pH.A mixture of isomers are generated, in which the trans—trans isgenerally preferred.

Scheme XIX describes several strategies for resolving the racemicpyrrolidines described above. Treatment with a chiral acid, for example(S)-(+)-mandelic acid, may provide a crystalline derivative, which canbe further enriched through recrystallization. The salt may be washedwith base to extract the resolving agent and return the optically activepyrrolidine product. Alternatively, the amino ester can be N-protected(for example with Boc-anhydride) and hydrolyzed (for example with sodiumhydroxide) to give the corresponding N-protected amino acid. Activationof the acid, for example as the pentafluorophenyl ester, followed bycoupling with a chiral nonracemic oxazolidinone anion, provides thecorresponding acyloxazolidinone diastereomers, which may be separatedchromatographically. Alcoholysis of one acyloxazolidinone diastereomer,followed by cleavage of the N-protecting group, returns an opticallyenriched amino ester. A similar transformation may be accomplishedthrough coupling of the protected amino acid with a chiral nonracemicamino alcohol. After chromatographic separation of the resultantdiastereomers, the amide is cleaved and the protecting group is removedto provide optically enriched product.

Optically active amino esters prepared as described above may bealkylated (Scheme XX) with a variety of electrophiles, for exampledibutyl bromoacetamide, N-butyl,N-alkoxy bromoacetamide,N-(4-heptyl)-N-(3-methyl-4-fluorophenyl) bromoacetamide, orN-(Ω-hydroxyalkyl)-N-alkyl haloacetamide. Hydrolysis of the resultantester, for example using sodium hydroxide in aqueous alcohol, providesthe product.

For one particular class of electrophile, N-(Ω-hydroxyalkyl)-N-alkylhaloacetamides, further transformations of the alkylation product arepossible (Scheme XXI). Activation (for example using methanesulfonylchloride) of the alcohol, followed by displacement with halogen (forexample, using lithium bromide) provides the corresponding halide.Displacement of halide with an amine, for example dimethylamine,provides the corresponding amino ester, which may be hydrolyzed aspreviously described to provide product.

Compounds which are useful as intermediates for the preparation ofcompounds of the invention are:

wherein n is 0 or 1;

m is 0 to 6;

W is (a) —C(O)₂—G where G is hydrogen or a carboxy protecting group,

(b) —PO₃H₂,

(c) —P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,

(d) —CN,

(e) —C(O)NHR₁₇ where R₁₇ is loweralkyl,

(f) alkylaminocarbonyl,

(g) dialkylaminocarbonyl,

(h) tetrazolyl,

(i) hydroxy,

(j) alkoxy,

(k) sulfonamido,

(l) —C(O)NHS(O)₂R₁₆ where R₁₆ is loweralkyl, haloalkyl, phenyl ordialkylamino,

(m) —S(O)₂NHC(O)R₁₆,

R₁ and R₂ are independently selected from hydrogen, loweralkyl, alkenyl,alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl,haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl,cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl,dialkylaminocarbonylalkyl, aminocarbonylalkenyl,alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl,aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl,(N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic,(heterocyclic)alkyl and (R_(aa))(R_(bb))N—R_(cc)— wherein R_(aa) is arylor arylalkyl, R_(bb) is hydrogen or alkanoyl and R_(cc) is alkylene,with the proviso that one or both of R₁ and R₂ is other than hydrogen;

or a salt thereof;

or a compound of the formula:

wherein n is 0 or 1;

m is 0 to 6;

W is (a) —C(O)₂—G where G is hydrogen or a carboxy protecting group,

(b) —PO₃H₂,

(c) —P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,

(d) —CN,

(e) —C(O)NHR₁₇ where R₁₇ is loweralkyl,

(f) alkylaminocarbonyl,

(g) dialkylaminocarbonyl,

(h) tetrazolyl,

(i) hydroxy,

(j) alkoxy,

(k) sulfonamido,

(l) —C(O)NHS(O)₂R₁₆ where R₁₆ is loweralkyl, haloalkyl, phenyl ordialkylamino,

(m) —S(O)₂NHC(O)R₁₆,

R₁ and R₂ are independently selected from hydrogen, loweralkyl, alkenyl,alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl,haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl,cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl,dialkylaminocarbonylalkyl, alklayminocarbonylalkenyl,alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl,aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl,(N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic,(heterocyclic)alkyl and (R_(aa))(R_(bb))N—R_(cc)— wherein R_(aa) is arylor arylalkyl, R_(bb) is hydrogen or alkanoyl and R_(cc) is alkylene,with the proviso that one or both of R₁ and R₂ is other than hydrogen;

or a salt thereof.

Preferred intermediates include compounds of formula (III), (IV) and (V)wherein

m is zero or 1;

W is —CO₂—G wherein G is hydrogen or a carboxy protecting group,

and R₁ and R₂ are as defined above; or

the substantially pure (+)- or (−)-isomer thereof.

Particularly preferred intermediates are compounds of formula (III),(IV) and (V) wherein

n and m are both 0;

W is —CO₂—G wherein G is hydrogen or a carboxy protecting group;

and R₁ is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv)cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii)substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl,3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl,4-trifluoromethylphenyl, 4-pentafluoroethylphenyl,3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl,4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl,1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein thesubstituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxyand carboxyalkoxy (ix) aryalkyl, (x) aryloxyalkyl, (xi) heterocyclic(alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, and (xiii)alkylsulfonylamidoalkyl, and R₂ is substituted or unsubstituted1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl,8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl,4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl whereinthe substituent is selected from loweralkyl, alkoxy and halogen; or

the substantially pure (+)- or (−)-isomer thereof.

Other compounds which are useful as intermediates for the preparation ofcompounds of the invention are:

wherein n is 0 or 1;

m is 0 to 6;

R_(5b) is alkylene;

Q is a leaving group;

W is (a) —C(O)₂—G where G is hydrogen or a carboxy protecting group,

(b) —PO₃H₂,

(c) —P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,

(d) —CN,

(e) —C(O)NHR₁₇ where R₁₇ is loweralkyl,

(f) alkylaminocarbonyl,

(g) dialkylaminocarbonyl,

(h) tetrazolyl,

(i) hydroxy,

(j) alkoxy,

(k) sulfonamido,

(l) —C(O)NHS(O)₂R₁₆ where R₁₆ is loweralkyl, haloalkyl, phenyl ordialkylamino,

(m) —S(O)₂NHC(O)R₁₆,

R₁ and R₂ are independently selected from hydrogen, loweralkyl, alkenyl,alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl,haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl,cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl,dialkylaminocarbonylalkyl, aminocarbonylalkehyl,alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl,aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl,(N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic,(heterocyclic)alkyl and (R_(aa))(R_(bb))N—R_(cc)— wherein R_(aa) is arylor arylalkyl, R_(bb) is hydrogen or alkanoyl and R_(cc) is alkylene,with the proviso that one or both of R₁ and R₂ is other than hydrogen;

or a salt thereof;

or a compound of the formula:

wherein n is 0 or 1;

m is 0 to 6;

R_(5b) is alkylene;

Q is a leaving group;

W is (a) —C(O)₂—G where G is hydrogen or a carboxy protecting group,

(b) —PO₃H₂,

(c) —P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,

(d) —CN,

(e) —C(O)NHR₁₇ where R₁₇ is loweralkyl,

(f) alkylaminocarbonyl,

(g) dialkylaminocarbonyl,

(h) tetrazolyl,

(i) hydroxy,

(j) alkoxy,

(k) sulfonamido,

(l) —C(O)NHS(O)₂R₁₆ where R₁₆ is loweralkyl, haloalkyl, phenyl ordialkylamino,

(m) —S(O)₂NHC(O)R₁₆,

R₁ and R₂ are independently selected from hydrogen, loweralkyl, alkenyl,alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl,haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl,cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl,dialkylaminocarbonylalkyl, aminocarbonylalkenyl,alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl,aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl,(N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic,(heterocyclic)alkyl and (R_(aa))(R_(bb))N—R_(cc)— wherein R_(aa) is arylor arylalkyl, R_(bb) is hydrogen or alkanoyl and R_(cc) is alkylene,with the proviso that one or both of R₁ and R₂ is other than hydrogen;

or a salt thereof.

Preferred intermediates include compounds of formula (VI), (VII) and(VIII) wherein

m is zero or 1;

R_(5b) is alkylene;

Q is a leaving group;

W is —CO₂—G wherein G is hydrogen or a carboxy protecting group, and R₁and R₂ are as defined above; or

the substantially pure (+)- or (−)-isomer thereof.

Particularly preferred intermediates are compounds of formula (VI),(VII) and (VIII) wherein

n and m are both 0;

R_(5b) is alkylene;

Q is a leaving group;

W is —CO₂—G wherein G is hydrogen or a carboxy protecting group; and R₁is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v)phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted orunsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl,4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl,4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl,3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl,4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanylor dihydrobenzofuranyl wherein the substituent is selected fromloweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix)aryalkyl, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii)(N-alkanoyl-N-alkyl)aminoalkyl, and (xiii) alkylsulfonylamidoalkyl, andR₂ is substituted or unsubstituted 1,3-benzodioxolyl,7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl,8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl,4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl whereinthe substituent is selected from loweralkyl, alkoxy and halogen; or

the substantially pure (+)- or (−)-isomer thereof.

Other compounds which are useful as intermediates for the preparation ofcompounds of the invention are:

wherein n is 0 or 1;

m is 0 to 6;

R_(5b) is alkylene;

R_(20a) is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl,haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl;

W is (a) —C(O)₂—G where G is hydrogen or a carboxy protecting group,

(b) —PO₃H₂,

(c) —P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,

(d) —CN,

(e) —C(O)NHR₁₇ where R₁₇ is loweralkyl,

(f) alkylaminocarbonyl,

(g) dialkylaminocarbonyl,

(h) tetrazolyl,

(i) hydroxy,

(j) alkoxy,

(k) sulfonamido,

(l) —C(O)NHS(O)₂R₁₆ where R₁₆ is loweralkyl, haloalkyl, phenyl ordialkylamino,

(m) —S(O)₂NHC(O)R₁₆,

R₁ and R₂ are independently selected from hydrogen, loweralkyl, alkenyl,alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl,haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl,cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl,dialkylaminocarbonylalkyl, aminocarbonylalkenyl,alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl,aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl,(N-alkanoyl-N-alkyl)arninoalkyl, alkylsulfonylamidoalkyl, heterocyclic,(heterocyclic)alkyl and (R_(aa))(R_(bb))N—R_(cc)— wherein R_(aa) is arylor arylalkyl, R_(bb) is hydrogen or alkanoyl and R_(cc) is alkylene,with the proviso that one or both of R₁ and R₂ is other than hydrogen;

or a salt thereof;

or a compound of the formula:

wherein n is 0 or 1;

m is 0 to 6;

R_(5b) is alkylene;

R_(20a) is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl,haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl;

W is (a) —C(O)₂—G where G is hydrogen or a carboxy protecting group,

(b) —PO₃H₂,

(c) —P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,

(d) —CN,

(e) —C(O)NHR₁₇ where R₁₇ is loweralkyl,

(f) alkylaminocarbonyl,

(g) dialkylaminocarbonyl,

(h) tetrazolyl,

(i) hydroxy,

(j) alkoxy,

(k) sulfonamido,

(l) —C(O)NHS(O)₂R₁₆ where R₁₆ is loweralkyl, haloalkyl, phenyl ordialkylamino,

(m) —S(O)₂NHC(O)R₁₆,

R₁ and R₂ are independently selected from hydrogen, loweralkyl, alkenyl,alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl,haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl,cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl,dialkylaminocarbonylalkyl, aminocarbonylaikenyl,alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl,aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl,(N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic,(heterocyclic)alkyl and (R_(aa))(R_(bb))N—R_(cc)— wherein R_(aa) is arylor arylalkyl, R_(bb) is hydrogen or alkanoyl and R_(cc) is alkylene,with the proviso that one or both of R₁ and R₂ is other than hydrogen;

or a salt thereof.

Preferred intermediates include compounds of formula (IX), (X) and (XI)wherein

m is zero or 1;

R_(5b) is alkylene;

R_(20a) is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl,haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl;

W is —CO₂—G wherein G is hydrogen or a carboxy protecting group, and R₁and R₂ are as defined above; or

the substantially pure (+)- or (−)-isomer thereof.

Particularly preferred intermediates are compounds of formula (IX), (X)and (XI) wherein

n and m are both 0;

R_(5b) is alkylene;

R_(20a) is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl,haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl;

W is —CO₂—G wherein G is hydrogen or a carboxy protecting group; and R₁is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v)phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted orunsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl,4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl,4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl,3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl,4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanylor dihydrobenzofuranyl wherein the substituent is selected fromloweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix)aryalkyl, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii)(N-alkanoyl-N-alkyl)aminoalkyl, and (xiii) alkylsulfonylamidoalkyl, andR₂ is substituted or unsubstituted 1,3-benzodioxolyl,7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl,8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl,4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl whereinthe substituent is selected from loweralkyl, alkoxy and halogen; or

the substantially pure (+)- or (−)-isomer thereof.

The foregoing may be better understood by reference to the followingexamples which are provided for illustration and not intended to limitthe scope of the inventive concept. The following abbreviations areused: Boc for tert-butyloxycarbonyl, Cbz for benzyloxycarbonyl, DBU for1,8-diazabicyclo[5.4.0]undec-7-ene, EDCl for1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride, EtOAc forethyl acetate, EtOH for ethanol, HOBt for 1-hydroxybenzotriazole, Et₃Nfor triethylamine, TFA for trifluoroacetic acid and THF fortetrahydrofuran.

EXAMPLE 1trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(propylaminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid EXAMPLE 1A Ethyl2-(4-Methoxybenzoyl)-4-nitromethyl-3-(1,3-benzodioxole-5-yl)butyrate

To ethyl (4-methoxybenzoyl)acetate (23.0 g, 0.104 mol), prepared by themethod of Krapcho et al., Org. Syn. 47, 20 (1967), and5-(2-nitrovinyl)-1,3-benzodioxole (17.0 g, 0.088 mol) dissolved in 180mL of toluene and heated to 80° C. was added 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU, 0.65 g) with stirring. The mixture was heated untilall the nitro starting material dissolved. The solution was stirredwithout heating for 30 minutes (min) and then an additional 0.65 g ofDBU was added. After stirring an additional 45 minutes, thin layerchromatography (5% ethyl acetate in methylene chloride) indicated theabsence of nitro starting material. Toluene (200 mL) was added, and theorganic phase was washed with dilute hydrochloric acid and NaClsolution. The organic phase was dried over sodium sulfate and thenconcentrated under reduced pressure. The residue obtained waschromatographed on silica gel eluting with 3:1 hexane-ethyl acetate togive 21.22 g of the desired product as a mixture of isomers and 9.98 g.of recovered ethyl (4-methoxybenzoyl)acetate.

EXAMPLE 1B Ethyl2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-4,5-dihydro-3H-pyrrole-3-carboxylate

The compound resulting from Example 1A (21 g) in 500 mL of ethanol washydrogenated under 4 atmospheres of hydrogen pressure using a Raneynickel 2800 catalyst (51 g). (The Raney nickel was washed with ethanolthree times before use.) The catalyst was removed by filtration, and thesolution was concentrated under reduced pressure. The residue obtainedwas chromatographed on silica gel eluting with 8.5% ethyl acetate inmethylene chloride to give 12.34 g of the desired product.

EXAMPLE 1C Ethyl2-(4-Methoxyphenyl-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate)as a Mixture of cis—cis: trans,trans; and cis,trans-Isomers

The compound resulting from Example 1B (11.89 g, 0.324 mol) wasdissolved in 27 mL of tetrahydrofuran and 54 mL of ethanol. Sodiumcyanoborohydride (2.35 g, 0.374 mol) and 5 mg bromocresol green wereadded. To this blue solution was added dropwise a solution of 1:2concentrated HCl in ethanol at such a rate that the color was kept atlight yellow-green. After the yellow color persisted without additionalHCl, the solution was stirred an additional 20 minutes. The solution wasconcentrated in vacuo and then partitioned between chloroform and anaqueous potassium bicarbonate solution. The organic phase was separated,dried over sodium sulfate, and concentrated under reduced pressure. Theresidue was chromatographed on silica gel eluting with 85:15 ethylacetate-hexane to give 5.96 g. of a mixture of 64% trans,trans-compoundand 34% cis,trans-compound. Further elution with pure ethyl acetate gave0.505 g of an unknown solid followed by 3.044 g of purecis,cis-compound.

EXAMPLE 1Dtrans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(propylaminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

The mixture of 64% trans,trans- and 34% cis,trans-pyrrolidines (themixture resulting from Example 1C) (5.72 g, 15.50 mmol),ethyldiisopropylamine (4.20 g, 32.56 mmol), and N-propyl bromoacetamide(3.42 g, 19.0 mmol), prepared by the method of Weaver, W. E. and Whaley,W. M., J. Amer. Chem. Soc., 69: 515 (1947), in 30 mL of acetonitrile washeated at 50° C. for 1 hour. The solution was concentrated in vacuo. Theresidue was dissolved in toluene, shaken with potassium bicarbonatesolution, dried over sodium sulfate and concentrated in vacuo to give7.16 g of product as a mixture of trans,trans- and cis,trans- ethylesters.

This mixture was dissolved in a solution of 50 mL of ethanol and 15 mLof water containing 5.00 g of sodium hydroxide and stirred for 3 hoursat room temperature. The solution was concentrated in vacuo and 60 mL ofwater added. The mixture was extracted with ether to remove theunreacted cis,trans- ethyl ester. The aqueous phase was treated withhydrochloric acid until slightly cloudy. It was then further neutralizedwith acetic acid to give the crude acid product. The crude product wasfiltered and purified by dissolving it in tetrahydrofuran, drying oversodium sulfate, concentrating in vacuo, and crystallizing from ether togive 3.230 g of the title compound. m.p. 151-153° C. ¹H NMR (CD₃OD, 300MHz) δ 0.87 (t, J=7 Hz, 3H), 1.49 (sextet, J=7 Hz, 2H), 2.84 (d, J=16Hz, 1H), 2.95-3.20 (m, 4H), 3.20 (d, J=16 Hz, 1H), 3.34-3.42 (m, 1H),3.58-3.66 (m, 1H), 3.78 (s, 3H), 3.88 (d, J=10 Hz, 1H), 5.92 (s, 2H),6.75 (d, J=8 Hz, 1H), 6.86 (dd, J=8 Hz, J=1 Hz, 1H), 6.90 (d, J=9 Hz,2H), 7.02 (d, J=1 Hz, 1H), 7.40 (d, J=9 Hz, 2H).

EXAMPLE 2trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(aminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

Using the method described in Example 1D, 300 mg of the mixture of 64%trans,trans- and 34% cis,trans-pyrrolidines (the mixture resulting fromExample 1C), 220 mg of diisopropylethylamine and 184 mg iodoacetamidewere reacted at 45° C. in 1 mL acetonitrile to give 291 mg of a mixtureof trans,trans- and cis,trans- N-alkylated esters. A portion (270 mg.)was hydrolyzed with 200 mg NaOH in 1 mL of water and 3 mL of ethanol; achloroform extraction was used to remove the unreacted cis,trans- ethylester. The isolation and purification procedures described in Example 1Dwere used to give 134 mg of the title compound. m.p. 246-248° C. ¹H NMR(DMSO-d₆, 300 MHz) δ 2.61 (d, J=16 Hz, 1H), 2.71 (t, J=9 Hz, 1H), 2.90(t, J=9 Hz, 1H), 2.98 (d, J=16 Hz, 1H),3.25-3.35 (m, 1H), 3.45-3.55 (m,1H), 3.71 (s, 3H), 3.75 (d, J=10 Hz, 1H), 6.00 (s, 2H), 6.81 (s, 2H),6.90 (d, J=8 Hz, 2H), 7.10 (s, 1H), 7.17 (s, 1H), 7.34 (s, 1H), 7.38 (d,J=8 Hz, 2H).

EXAMPLE 3trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(4-fluorobenzyl-pyrrolidine-3-carboxylicAcid

Using the method described in Example 1D, 300 mg of the mixture of 64%trans,trans- and 34% cis,trans- pyrrolidines (the mixture resulting fromExample 1C), 220 mg of diisopropylethylamine and 185 mg of4-fluorobenzyl bromide were reacted at room temperature for 3 hours in 1mL of acetonitrile to give 387 mg of a mixture of trans,trans- andcis,trans-N-alkylated esters. A portion (360 mg) was hydrolyzed with 250mg NaOH in 1 mL of water and 4 mL of ethanol to give 160 mg of the titlecompound as an amorphous powder. ¹H NMR (CDCl₃, 300 MHz) δ 2.74 (t, J=9Hz, 1H), 2.95 (t, J=7 Hz, 1H), 2.98 (d, J=14, 1H), 3.07 (dd, J=9 Hz, 1Hz, 1H), 3.42-3.53 (m, 1H), 3.70 (d, J=9 Hz, 1H), 3.78 (d, J=14, 1H),3.81 (s, 3H), 5.92 (s, 2H), 6.70 (d, J=8 Hz, 1H), 6.77 (dd, J=8 Hz, 1Hz, 1H), 6.91 (d, J=9 Hz, 2H), 6.94 -7.00 (m, 3H), 7.20-7.25 (M, 1H),7.44 (d, J=9 Hz, 2H).

EXAMPLE 4trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-ethoxyethyl)-pyrrolidine-3-carboxylicAcid

Using the method described in Example 1D, 300 mg. of the mixture of 64%trans,trans- and 34% cis,trans-pyrrolidines (the mixture resulting fromExample 1C), 220 mg of diisopropylethylamine and 152 mg of 2-bromoethylethyl ether were refluxed in 1.5 mL acetonitrile for 3 hours (bathtemperature at 95° C.) to give 346 mg of a mixture of trans,trans- andcis,trans-esters. Hydrolysis with 250 mg NaOH in 1 mL of water and 3 mLof ethanol afforded 140 mg of the title compound. m.p. 88-90° C. ¹H NMR(CDCl₃, 300 MHz) δ 1.25 (t, J=7 Hz, 3H), 2.21-2.32 (m, 1H), 2.70-2.80(m, 1H), 2.85-2.94 (m, 2H), 3.38-3.55 (m, 6H), 3.67 (d, J=10 Hz, 1H),3.79 (s, 3H), 5.94 (s, 2H), 6.72 (d, J=8 Hz, 1H), 6.84 (m, 1H), 6.84 (d,J=9 Hz, 2H), 7.08 (d, J=1 Hz, 1H), 7.33 (d, J=9 Hz, 2H).

EXAMPLE 5trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-propoxyethyl)-pyrrolidine-3-carboxylicAcid

Using the method described in Example 1D, 520 mg of the mixtureresulting from Example 1C, 364 mg of diisopropylethylamine, 50 mgpotassium iodide and 350 mg 2-chloroethyl propyl ether were reacted at125° C. in 0.5 mL acetonitrile for 4 hours to give 517 mg of a mixtureof trans,trans- and cis,trans-esters. A portion (500 mg) was hydrolyzedwith 315 mg NaOH in 1 mL of water and 4 mL of ethanol to give 225 mg ofthe title compound as an amorphous powder. ¹H NMR (CDCl₃, 300 MHz) δ0.87 (t, J=7 Hz, 3H), 1.53 (sextet, J=7 Hz, 2H), 2.28-2.41 (m, 1H),2.71-2.83 (m, 1H), 2.92-3.08 (m, 2H), 3.30 (t, J=7 Hz, 2H), 3.40-3.60(m, 4H), 3.72-3.83 (m, 1H), 3.76 (s, 3H), 5.92 (s, 2H), 6.71 (d, J=8 Hz,2H), 6.74 (dd, J=8 Hz, 1 Hz), 6.71 (d, J=9 Hz, 2H), 7.07 (d, J=9 Hz,2H), 7.73 (d, J=9 Hz, 2H).

EXAMPLE 6trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(2-methoxyethoxy)ethyl]-pyrrolidine-3-carboxylicAcid EXAMPLE 6A Ethyltrans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylate

To the pure cis,cis-compound resulting from Example 1C (3.02 g)dissolved in 10 mL of ethanol was added 20 drops of a solution of 21%sodium ethoxide in ethanol. The reaction mixture was refluxed overnight,at which time thin layer chromatography in ethyl acetate indicated theabsence of starting material. The NaOEt was neutralized with HCl inethanol, and the solution was concentrated in vacuo. The residue wastaken up in toluene and extracted with potassium bicarbonate in water.The toluene was dried over sodium sulfate and concentrated under reducedpressure to give 2.775 of the title compound which was pure by TLC(ethyl acetate).

EXAMPLE 6Btrans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(2-methoxyethoxy)ethyl]-pyrrolidine-3-carboxylicAcid

Using the method described in Example 1D, 250 mg of the compoundresulting from Example 6A, 150 mg of 2-(2-methoxyethoxy)ethyl bromideand 175 mg diisopropyl-ethylamine in 1 mL acetonitrile were heated at100° C. for 3 hours to give 229 mg of the trans,trans-ester. A portion(200 mg) was hydrolyzed with 125 mg NaOH in 1 mL of water and 2 mL ofethanol to give 151 mg of the title compound as an amorphous powder. ¹HNMR (CD₃OD, 300 MHz) δ 2.9-3.9 (m, 13H), 3.81 (s, 3H), 4.49 (d, J=10 Hz,1H), 5.94 (s, 2H), 6.79 (d, J=8 Hz, 1H), 6.89 (dd, J=8 Hz, 1 Hz, 1H),7.00 (d, J=9 Hz, 2H), 7.05 (d, J=1 Hz, 1H), 7.49 (d, J=9 Hz, 2H).

EXAMPLE 7trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(2-pyridyl)ethyl]-pyrrolidine-3-carboxylicAcid

The compound resulting from Example 6A (250 mg), 2-vinyl pyridine (355mg) and one drop of acetic acid were dissolved in 2-methoxyethanol, andstirred at 100° C. for 2.5 hours. Toluene was added, and the solutionwas washed with potassium bicarbonate solution. The solution was driedover potassium bicarbonate and concentrated in vacuo. Toluene was addedand the solution re-concentrated. This was done until the odor of2-vinylpyridine was gone. The residue was taken up in hot heptane,filtered to remove a small amount of insoluble impurity, andconcentrated in vacuo to give 225 mg of intermediate ester. The esterwas hydrolyzed by the method described in Example 1D to give 202 mg ofthe title compound as the dihydrate. m.p. 77-80° C. ¹H NMR (CD₃OD, 300MHz) δ 2.8-3.3 (m, 6H), 3.55-3.70 (m, 2H), 3.76 (s, 3H), 3.99 (d, J=10Hz, 1H), 5.92 (d, J=1 Hz, 2H), 6.72 (d, J=8 Hz, 1H), 6.80 (dd, J=8 Hz, 1Hz), 6.85 (d, J=9 Hz, 2H), 6.92 (d, J=1 Hz, 1H), 7.20 (d, J=9 Hz, 2H),7.20-7.32 (m, 2H), 7.70-7.80 (m, 2H), 8.40 (d, J=4 Hz, 1H).

EXAMPLE 8trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(morpholin-4-ylcarbonyl)-pyrrolidine-3-carboxylicAcid

To the compound resulting from Example 6A (300 mg) and 164 mgtriethylamine dissolved in 2 mL of methylene chloride and cooled in anice bath was added 146 mg 1-morpholinocarbonyl chloride. The mixture wasstirred 3 hours at room temperature. Toluene- was added and the solutionwas washed with potassium bicarbonate solution, dried over sodiumsulfate and concentrated in vacuo to give the intermediate ester. Theester was hydrolyzed by the method described in Example 1D to give 288mg of the title compound. m.p. 244-246° C. ¹H NMR (DMSO-d₆, 300 MHz) δ2.96 (dd, J=12,Hz, 13 Hz, 1H), 3.03-3.13 (m, 2H), 3.20-3.30 (m, 2H),3.40-3.60 (m, 5H), 3.74 (s, 3H), 3.70-3.85 (m, 3H), 5.10 (d, J=10 Hz,1H), 5.99 (d, J=1 Hz, 2H), 6.80-6.90 (m, 2H), 6.87 (d, J=9 Hz, 2H), 7.07(s, 1H), 7.25 (d, J=9 Hz, 2H).

EXAMPLE 9trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxole-5-yl)-1-(butylaminocarbonyl)-pyrrolidine-3-carboxylicAcid

To the compound resulting from Example 6A (300 mg) dissolved in 2 mLtetrahydrofuran and cooled in an ice bath was added 88 mg of butylisocyanate. After 40 minutes at room temperature, toluene was added, andthe solution was concentrated in vacuo to give the intermediate ester.The ester was hydrolyzed by the method described in Example 1D to give232 mg of the title compound. m.p. 220-221° C. ¹H NMR (DMSO-d₆, 300 MHz)δ 0.78 (t, J=7 Hz, 3H), 1.10 (sextet, J=7 Hz, 2H), 1.22 (quintet, J=7Hz, 2H), 2.78-3.05 (m, 3H), 3.40-3.56 (m, 2H), 3.74 (s, 3H), 3.95-4.05(m, 1H), 4.93 (d, J=9 Hz, 1H), 5.80 (t, broad, J=7 Hz, 1H), 5.99 (s,2H), 6.78-6.86 (m, 2H), 6.88 (d, J=9 Hz, 2H), 7.00 (d, J=1 Hz, 1H), 7.12(d, J=9 Hz, 2H).

EXAMPLE 10trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(4-methoxyphenylaminocarbonyl)-3-pyrrolidine-3-carboxylicAcid

The compound resulting from Example 6A (300 mg) was treated with 133 mgof 4-methoxyphenyl isocyanate by the procedure described in Example 9.The resulting ester was hydrolyzed with NaOH using the method describedin Example 1D to give 279 mg of the title compound. m.p. 185-187° C. ¹HNMR (CDCl₃, 300 MHz) δ 3.23 (dd, J=12 Hz, 13 Hz, 1H), 3.55-3.68 (m, 2H),3.72 (s, 3H), 3.83 (s, 3H), 4.50-4.65 (m, 1H), 5.06 (d, J=10 Hz, 1H),5.90 (s, 1H), 5.95 (s, 1H), 6.72 (d, J=9 Hz, 2H), 6.7-6.8 (m, 3H), 6.92(d, J 9 Hz, 2H), 6.97 (d, J=9 Hz, 2H), 7.37 (d, J=9 Hz, 2H).

EXAMPLE 11trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-acetylpyrrolidine-3-carboxylicAcid

The compound resulting from Example 6A (250 mg) in 0.5 mL of toluene wastreated with 200 mg of acetic anhydride. After stirring 2 hours at roomtemperature, water was added and the acetic acid neutralized withpotassium bicarbonate. The mixture was extracted with toluene to give273 mg of the intermediate ester. A portion of the ester (200 mg) washydrolyzed using the method of Example 1D to give 211 mg of the titlecompound. m.p. 248-250° C. Rotational isomers are seen in the NMR. ¹HNMR (DMSO-d₆, 300 MHz) δ 1.55 and 2.00 (s, 3H), 2.94 and 3.03 (dd, J=12Hz, 13 Hz, 1H), 3.3-3.6 (m, 2H), 3.72 and 3.76 (s, 3H), 4.12 and 4.28(dd, J=12 Hz, 7 Hz, 1H), 4.95 and 5.04 (d, J=10Hz, 1H), 6.00 (s, 2H),6.75-6.87 (m, 3H), 6.95 and 7.04 (d, J=9 Hz, 2H), 7.18 and 7.32 (d, J=9Hz, 2H).

EXAMPLE 12trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-furoyl)-pyrrolidine-3-carboxylicAcid

To the compound resulting from Example 6A (300 mg) and 164 mgtriethylamine dissolved in 2 mL methylene chloride and cooled in an icebath was added 138 mg of 2-furoyl chloride. The mixture was stirred 30minutes at room temperature and then worked up by the proceduresdescribed in Example 8 to give the intermediare ester. The ester washydrolyzed by the procedure described in Example 1D to give 269 mg ofthe title compound as an amorphous powder. ¹H NMR (DMSO-d₆, 300 MHz) δ3.06 (dd, J=12 Hz, 13 Hz, 1H), 3.3-3.6 (m, 2H), 4.25 (m, 1H), 5.19 (d,J=10 Hz, 1H), 6.67.4 (m, 8H), 7.8-7.9 (m, 1H).

EXAMPLE 13trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(phenylaminocarbonyl)-pyrrolidine-3-carboxylicAcid

Starting with the compound resulting from Example 6A, phenyl isocyanateand the procedures described in Example 9, the title compound wasprepared. m.p. 209-211° C. ¹H NMR (DMSO-d₆, 300 MHz) δ 3.03 (dd, 1H),3.55 (m, 1H), 3.70 (m, 1H), 3.72 (s, 3H), 4.15 (m, 1H), 5.13 (d, 1H),6.00 (s, 2H), 6.88 (m, 5H), 7.07-7.20 (m, 3H), 7.30 (d, 2H), 7.38 (d,2H), 8.20 (bs, 1H).

EXAMPLE 14trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(allylaminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 1 the title compound wasprepared. m.p. 138-140° C. ¹ H NMR (CDCl₃, 300 MHz) δ 2.84 (d, 1H),2.90-3.10 (dt, 2H), 3.28 (d, 1H), 3.35 (dd, 1H), 3.62 (m, 1H), 3.72-3.97(m, 3H), 3.80 (s, 3H), 5.13 (bd, 2H), 5.80 (m, 1H), 5.97 (s, 2H),6.74-6.97 (m, 5H), 7.38 (d, 2H).

EXAMPLE 15trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(n-butylaminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 1 the title compound wasprepared. m.p. 105-107° C. ¹H NMR (CDCl_(3,) 300 MHz) δ 0.90 (t, 3H),1.30 (m, 2H), 1.45 (m, 2H), 2.80 (d, 1H), 2.87-3.35 (m, 6H), 3.62 (m,1H), 3.80 (s, 3H), 5.97 (s, 2H), 6.75-6.92 (m, 5H), 7.28 (d, 2H).

EXAMPLE 16trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-(n-propyl)-N-methylaminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 1 the title compound wasprepared as an amorphous solid. Rotational isomers are seen in the NMR.¹H NMR (CDCl₃, 300 MHz) δ 0.73, 0.84 (2t, 3H), 1.49 (m, 2H), 2.80 (dd,1H), 2.85 (2s, 3H), 2.95-3.20 (m, 3H), 3.20-3.40 (m, 1H), 3.40 (d, 1H),3.60 (m, 1H), 3.79 (s, 3H), 5.93 (s, 2H), 6.73 (d, 1H), 6.86 (m, 2H),7.03 (m, 1H), 7.32 (d, 2H).

EXAMPLE 17trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(pyrrolidin-1-ylcarbonylmethyl)-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 1 the title compound wasprepared as an amorphous solid. ¹H NMR (COCl₃, 300 MHz) δ 1.40-1.70 (m,6H), 2.80 (d, 1H), 3.00 (m, 2H), 3.24-3.43 (m, 5H), 3.60 (m, 2H), 3.73(d, 1H), 3.80 (s, 3H), 5.95 (s, 2H), 6.74 (d, 1H), 6.80-6.90 (m, 3H),7.04 (d, 1H), 7.30 (d, 2H).

EXAMPLE 18trans,trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1-(isobutylaminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 1 the title compound wasprepared. m.p. 175-177° C. ¹H NMR (CD₃OD, 300 MHz) δ 0.87 (dd, 6H), 1.75(septet, 1H), 2.85 (d, 1H), 2.90-3.10 (m, 4H), 3.23 (d, 1H), 3.40 (m,1H), 3.58-3.67 (m, 1H), 3.78 (s, 3H), 3.89 (d, 1H), 5.92 (s, 2H), 6.76(d, 1H), 6.86 (dd, 1H), 6.91 (d, 2H), 7.02 (d, 1H), 7.40 (d, 2H).

EXAMPLE 19trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(cyclopentylaminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 1 the title compound wasprepared. m.p. 137-139° C. ¹H NMR (CDCl₃, 300 MHz) δ 1.34 (m, 2H), 1.62(m, 4H), 1.90 (m, 2H), 2.76 (d, 1H), 2.90 (t, 1H), 3.04 (dd, 1H), 3.22(d, 1H), 3.28 (dd, 1H), 3.40 (m, 1H), 3.80 (s, 3H), 4.15(m, 1H), 5.97(d, 2H), 6.75-6.95 (m, 5H), 7.27 (m, 2H).

EXAMPLE 20 trans,trans-2-(4-Methoxyphenyl)-4-(13-benzodioxol-5-yl)-1-(morpholin-4-ylaminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 1 the title compound wasprepared as an amorphous solid. ¹H NMR (CDCl₃, 300 MHz) δ 2.82 (d, 1H),3.00 (m, 2H), 3.24 (m, 1H), 3.30-3.52 (m, 4H), 3.52-3.75 (m, 8H), 3.80(s, 3H), 5.95 (s, 2H), 6.75 (d, 1H), 6.84 (d, 3H), 7.00 (s, 1H), 7.28(d, 2H).

EXAMPLE 21trans,trans-2-(4-Methoxyohenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-phenoxyethyl)-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 4 the title compound wasprepared as an amorphous solid. ¹H NMR (CD₃OD, 300 MHz) δ 2.82 (m, 1H),2.96 (dd, 1H), 3.13 (m, 1H), 3.32 (m, 1H), 3.51-3.70 (m, 2H), 3.77 (s,3H), 4.00 (d, 1H), 4.07 (m, 2H), 5.91 (s, 2H), 6.72 (d, 1H), 6.80-6.95(m, 6H), 7.03 (d, 1H), 7.22 (dd, 2H), 7.39 (d, 2H).

EXAMPLE 22trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-methoxyethylaminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 1 the title compound wasprepared. m.p. 107-109° C. ¹H NMR (CD₃OD, 300 MHz) δ 2.82 (d, 1H), 2.97(q, 2H), 3.21 (d, 1H), 3.38 (m, 1H), 3.32 (s, 3H), 3.44 (m, 4H), 3.62(m, 1H), 3.79 (s, 3H), 3.86 (d, 1H), 5.93 (s, 2H), 6.76 (d, 1H), 6.85(dd, 1H), 6.91 (d, 2H), 7.01 (d, 1H), 7.38 (d, 2H).

EXAMPLE 23trans,trans-2-(4-Methoxyohenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-butoxyethyl)-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 4 the title compound wasprepared. m.p. 53-55° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.88 (t, J=7 Hz, 3H),1.32 (sextet, J=7 Hz, 2H), 1.50 (pentet, J=7 Hz, 2H), 2.27 (tt, J=6 Hz,6 Hz, 1H), 2.92 (q, J=10 Hz, 2H), 3.35 (t, J=7 Hz, 2H), 3.42-3.56 (m,4H), 3.68 (d, J=10 Hz, 1H), 3.78 (s, 3H), 5.94 (s, 2H), 6.73 (d, J=8 Hz,1H), 6.83 (d, J=9 Hz, 2H), 6.82-6.87 (m, 1H), 7.06 (d, J=2 Hz, 1H), 7.32(d, J=9 Hz, 2H). MS m/e 442 (M+H)⁺.

EXAMPLE 24trans,trans-2-(1,3-Benzodioxol-5-yl)-4-(4-methoxyphenyl)-1-(propylaminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 1 and substituting ethyl(1,3-benzodioxol-5-ylcarbonyl)acetate for ethyl(4-methoxybenzoyl)acetate and 4-(2-nitrovinyl)anisole for5-(2-nitrovinyl)-1,3-benzodioxol-5yl afforded the title compound. m.p.97-99° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.78 (t, J=7 Hz, 3H), 1.39 (sextet,J=7 Hz, 2H), 2.72 (d, J=16 Hz, 1H), 2.74 (t, J=10 Hz, 1H), 2.80-3.10 (m,4H), 3.26-3.38 (m, 1H), 3.53 (m, 1H), 3.73 (s, 3H), 3.80 (d, J=10 Hz,2H), 7.80 (t, J=6 Hz, 1H). MS (DCl/NH₃) m/e 441 (M+H)⁺.

EXAMPLE 25trans,trans-2-(1,3-Benzodioxol-5-yl)-4-(4-methoxyphenyl)-1-(2-propoxyethyl)-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 5 and substituting ethyl(1,3-benzodioxol-5-ylcarbonyl)acetate for ethyl(4-methoxybenzoyl)acetate and 4-(2-nitrovinyl)anisole for5-(2-nitrovinyl)-1,3-benzodioxol-5yl afforded the title compound. m.p.67-69° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.89 (t, J=7 Hz, 3H), 1.56 (sextet,J=7 Hz, 2H), 2.33 (m, 1H), 2.78-3.00 (m, 3H), 3.32 (t, J=7 Hz, 2H),3.45-3.57 (m, 4H), 3.73 (m, 1H), 3.79 (s, 3H), 5.93 (s, 2H), 6.22 (d,J=8 Hz, 1H), 6.85 (d, J=8 Hz, 3H), 6.98 (s, 1H), 7.37 (d, J=8 Hz, 2H).MS (DCl/NH₃) m/e 428 (M+H)⁺.

EXAMPLE 26trans,trans-2-(1,3-Benzodioxol-5-yl)-4-(4-methoxyphenyl)-1-[2-(2-methoxyethoxy)ethyl)]-1-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 4 and substituting thestarting materials described in Example 25 and using2-(2-methoxyethoxy)ethylbromide to alkylate the pyrrolidine nitrogenafforded the title compound. m.p. 85-86° C. ¹H NMR (CD₃OD, 300 MHz) δ3.18-3.90 (m, 15H), 3.79 (s, 3H), 4.57 (d, J=10 Hz, 1H), 6.02 (s, 2H),6.91 (d, J=8 Hz, 1H), 6.95 (d, J=9 Hz, 2H), 7.06 (dd, J=8 Hz, 1H), 7.12(dd, J=1 Hz, 1H), 7.37 (d, J=9 Hz, 2H). MS (DCl/NH₃) m/e 444 (M+H)⁺.

EXAMPLE 27trans,trans-2-(1,3-Benzodioxol-5-yl)-4-(4-methoxyphenyl)-1-(butoxyethyl)-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 4, substituting the startingmaterials described in Example 25 and using 2-ethoxyethylbromide toalkylate the pyrrolidine nitrogen afforded the title compound. m.p.54-56° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.89 (t, J−7 Hz, 3H), 1.44 (sextet,J=7 Hz, 2H), 1.52 (pentet, J=7 Hz, 2H), 2.40 (m, 1H), 2.74-2.98 (m, 3H),3.46 (t, J=7 Hz, 2H), 3.42-3.56 (m, 4H), 3.68 (d, J=10 Hz, 1H), 3.80 (s,3H), 5.93 (dd, J=6 Hz, 1 Hz, 2H), 6.72 (d, J=8 Hz, 1H), 6.74 (dd, J=9Hz, 3H), 6.96 (s, 1H), 7.36 (d, J=9 Hz, 2H).

EXAMPLE 28trans,trans-2-(4-Methoxyphenyl)-4-(1,4-benzodioxan-6-y)-1-(propylaminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 1 and substituting6-(2-nitrovinyl)-1,4-benzodioxane for 5-(2-nitrovinyl)-1,3-benzodioxoleafforded the title compound. m.p. 80-81° C. ¹H NMR (CDCl₃, 300 MHz) δ0.89 (t, J−7 Hz, 3H), 1.49 (sextet, J=7 Hz, 2H), 2.78 (d, J=16 Hz, 1H),2.92 (t, J=10 Hz, 1H), 3.05-3.43 (m, 5H), 3.24 (d, J=16 Hz, 1H),3.52-3.62 (m, 1H), 3.80 (s, 3H), 3.80 (t, J=10 Hz, 1H), 4.27 (s, 4H),6.74-6.93 (m, 5H), 7.29 (d, J=9 Hz, 2H). MS (DCl/NH₃) m/e 455 (M+H)⁺.

EXAMPLE 29trans,trans-2-(4-Methoxyphenyl)-4-(1,4-benzodioxan-6-yl)-1-(N-methyl-N-propylaminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 1, substituting6-(2-nitrovinyl)-1,4-benzodioxane for 5-(2-nitrovinyl)-1,3-benzodioxoleand alkylating the pyrrolidine nitrogen with N-methyl-N-propylbromoacetamide afforded the title compound. m.p. 74-76° C. Rotationalisomers are seen in the NMR. ¹H NMR (CDCl₃, 300 MHz) δ 0.73, 0.83 (2t,J=7 Hz, 3H), 1.48 (m, 2H), 2.78 (dd, 1H), 2.85 (2s, 3H), 2.96-3.15 (m,3H), 3.27-3.42 (m, 3H), 3.52-3.60 (m, 1H), 3.75 (d, 1H), 3.78 (s, 3H),4.22 (s, 4H), 6.80-6.98 (m, 5H), 7.32 (d, 2H). MS (DCl/NH₃) m/e 469(M+H)⁺.

EXAMPLE 30trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-butylaminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 1, the title compound wasprepared. Rotational isomers are seen in the NMR. ¹H NMR (CD₃OD, 300MHz) δ 0.86 (2t, 3H), 1.04-1.50 (m, 4H), 2.85 (2s, 3H), 2.93-3.20 (m,4H), 3.40 (m, 2H), 3.52 (dd, 1H), 3.60 (m, 1H), 3.80 (s, 3H), 3.85 (m,1H), 5.91 (s, 2H), 6.74 (d, 1H), 6.83-6.95 (m, 3H), 7.03 (dd, 1H), 7.35(dd, 2H).

EXAMPLE 31trans,trans-2-(4-Methoxy-2-methoxymethoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-butylaminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid EXAMPLE 31A Ethyl2-(4-Methoxy-2-methoxymethoxyphenyl-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate)

Using the procedures described in Examples 1A and 1B and substitutingethyl (4-methoxy-2-methoxymethoxybenzoyl)acetate for ethyl(4-methoxybenzoyl)acetate afforded ethyl2-(4-methoxy-2-methoxymethoxyphenyl)-4-(1,3-benzodioxol-5-yl)-4,5-dihydro-3H-pyrrole-3-carboxylate.

The above dihydro pyrrole carboxylate (3.0 g, 7.0 mmol) was dissolved in20 mL of methanol, treated with 500 mg of 10% Pd/C and placed underhydrogen atmosphere for 32 hours. The catalyst was removed by filtrationand the filtrate was concentrated under reduced pressure andchromatographed on silica gel eluting with ethyl acetate to afford thetitle compound (1.9 g, 63%) as the cis-cis isomer.

EXAMPLE 31Btrans,trans-2-(4-Methoxy-2-methoxyvmethoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1-(N-methyl-N-butylaminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

The compound resulting from Example 31A was epimerized by the proceduredescribed in Example 6A. The resulting trans,trans compound (100 mg,0.23 mmol) was then reacted by the procedures described in Example 1Dsubstituting N-methyl-N-butyl bromoacetamide for N-propyl bromoacetamideto give the title compound (75 mg, 62%). m.p. 65-67° C. Rotationalisomers are seen in the NMR. ¹H NMR (CDCl₃, 300 MHz) δ 0.64, 0.68 (2t,J=7 Hz, 3H), 1.14, 1.12 (2 sextet, .J=7 Hz, 2H), 1.40-1.48 (m, 2H),2.86, 2.89 (2s, 3H), 2.95-3.42 (m, 6H), 3.50 (s, 3H), 3.43-3.65 (m, 2H),3.78 (s, 3H), 4.30 (t, J=7 Hz, 1H), 5.09 (q, J=7 Hz, 2H), 5.92 (s, 2H),6.55 (dd, J=3 Hz, 1H), 6.68 (s, 1H), 6.72 (s, 1H), 6.85 (2t, J=1 Hz,1H), 7.04 (t, J=1 Hz, 1H), 7.42 (dd, J=3 Hz, 1H).

EXAMPLE 32trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(3-ethoxypropyl)-pyrrolidin-5-one-3-carboxylicAcid EXAMPLE 32A Ethyl2-(4-Methoxybenzoyl)-3-carbomethoxy-1,3-benzodioxole-5-propionate

To ethyl (4-methoxybenzoyl)acetate (4.44 g, 0.02 mmol) dissolved in 20mL of anhydrous THF was added in portions 480 mg of NaH. The mixture wasstirred for 30 minutes under nitrogen at ambient temperature. Methyl(1,3-benzodioxol-5-yl) bromoacetate (5.46 g, 0.02 mol) in 5 mL of THFwas added. The mixture was stirred overnight at ambient temperature,diluted with 200 mL of EtOAc, and washed with water and brine. Theorganic phase was dried over sodium sulfate and concentrated in vacuo toafford the title compound (7.67 g, 92%) which was used without furtherpurification.

EXAMPLE 32B Ethyl1-(3-Ethoxypropyl)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-4,5-dihydro-5-oxo-1H-pyrrole-3-carboxylate

A mixture of the compound resulting from Example 32A (700 mg, 1.69mmol), 3-ethoxypropylamine (348 mg, 3.38 mmol) and 1 mL of acetic acidin a sealed tube was heated for 18 hours at 125° C. After cooling thecontents of the tube to ambient temperature, 5 mL of water was added andthe mixture extracted with ethyl acetate (2×100 mL). The combinedorganic extracts were washed with saturated sodium bicarbonate solution,water and brine, dried over sodium sulfate and concentrated underreduced pressure. The residue obtained was chromatographed on silica geleluting with 3:2 hexane-ethyl acetate to give 330 mg (42%) of the titlecompound.

EXAMPLE 32C Ethyl1-(3-Ethoxypropyl)-2-(4-methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-pyrrolidin-5-one-3-carboxylate

The compound resulting from Example 32B (300 mg, 0.64 mmol) in 15 mL ofmethanol was reduced with 100 mg of 10% Pd/C under hydrogen for 3 hoursat ambient temperature. The catalyst was removed by filtration and thefiltrate was concentrated under reduced pressure to give the titlecompound.

EXAMPLE 32Dtrans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(3-ethoxypropyl)-pyrrolidin-5-one-3-carboxylicAcid

To the compound resulting from Example 32C (100 mg, 0.21 mmol) dissolvedin 1 mL of ethanol was added 3 drops of a solution of 21% sodiumethoxide in ethanol. The mixture was heated to 70-80° C. for 3 hours,and then a solution of sodium hydroxide (100 mg) in 1 mL of water wasadded and heating was continued for 1 additional hour. The reactionmixture was cooled to ambient temperature, the ethanol was removed underreduced pressure, and water was added to the residue which was washedwith ether. The aqueous layer was neutralized with 3 M HCl and allowedto stand overnight. The white crystalline solid was collected byfiltration to give the title compound (60 mg, 64%). m.p. 134-140° C. ¹HNMR (DMSO-d₆, 300 MHz) δ 1.04 (t, J=7 Hz, 3H), 1.55 (sextet, J=7 Hz,2H), 2.48-2.56 (m, 1H), 2.93 (dd, J=9 Hz, 1H), 3.25 (t, J=7 Hz, 2H),3.28-3.40 (m, 2H), 3.48-3.57 (m, 1H), 3.78 (s, 3H), 3.88 (d, J=10 Hz,1H), 4.72 (d, J=10 Hz, 1H), 6.02 (s, 2H), 6.74 (dd, J=8 Hz, 1 Hz, 1H),6.87 (d, J=8 Hz, 2H), 6.98 (d, J=8 Hz, 2H), 7.38 (d, J=8 Hz, 2H). MS(DCl/NH₃) m/e 442 (M+H)⁺.

EXAMPLE 33trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(3-methoxybenzyl)-pyrrolidin-5-one-3-carboxylicAcid

Following the procedures described in Example 32 and substituting3-methoxybenzylamine for 3-ethoxypropylamine afforded the title compound(123 mg, 65%). m.p. 150-152° C. ¹H NMR (CD₃OD, 300 MHz) δ 2.96 (dd, J=8Hz, 10 Hz, 1H), 3.72 (s, 3H), 3.80 (s, 3H), 4.06 (d, J=10 Hz, 1H), 4.58(d, J=8 Hz, 1H), 4.92 (q, J=16 Hz, 2H), 5.92 (s, 2H), 6.55-6.63 (m, 2H),6.82 (d, J=8 Hz, 4H), 6.94 (d, J=8 Hz, 2H), 7.15-7.22 (m, 3H). MS(DCl/NH₃) m/e 475 (M+H)⁺.

EXAMPLE 34trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-diisoamylaminocarbonylmethyl)-pyrrolidine-3carboxylicAcid

The title compound was prepared as an amorphous solid using theprocedures described in Example 1. ¹H NM R (CDCl₃, 300 MHz) δ 0.70-0.90(m, 12H), 1.10-1.60 (m, 10H), 2.75 (d, J=13 Hz, 1H), 2.90-3.10 (m, 4H),3.15-3.30 (m, 2H), 3.40 (d, J=10 Hz, 1H), 3.40-3.52 (m, 2H), 3.55-3.62(m, 1H), 3.75 (d, J=12 Hz, 1H), 3.79 (s, 3H), 5.93 (dd, J=1 Hz, 3 Hz,2H), 6.72 (d, J=8 Hz, 1H), 6.82-6.90 (m, 3H), 7.03 (d, J=2 Hz, 1H), 7.30(d, J=9 Hz, 2H).

EXAMPLE 35trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-dipentylaminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

The title compound was prepared as an amorphous solid using theprocedures described in Example 1. ¹H NMR (CDCl₃, 300 MHz) δ 0.82 (t,J=7 Hz, 6H), 0.95-1.03 (m, 2H), 1.10-1.30 (m, 8H), 1.40-1.51 (m, 2H),2.72 (d, J=13 Hz, 1H), 2.90-3.08 (m, 4H), 3.25-3.50 (m, 3H), 3.37 (d,J=13 Hz, 1H), 3.52-3,60 (m, 1H), 3.70 (J=10 Hz, 1H), 3.75 (s, 3H), 5.92(dd, J=2 Hz, 5 Hz, 2H), 6.72 (d, J=8 Hz, 1H), 6.80-6.88 (m, 3H), 7.03(d, J=2 Hz, 1H), 7.30 (d, J=9 Hz, 2H).

EXAMPLE 36trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(2-methoxyethyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

The title compound was prepared using the procedures described inExample 1. m.p. 120-122° C. ¹H NMR (CDCl₃, 300 MHz) δ 2.82 (d, J=13,1H), 2.94-3.08 (m, 2H), 3.12 (s, 3H), 3.23 (s, 3H), 3.20-3.70 (m, 11H),3.73 (d, J=10 Hz, 1H), 3.79 (s, 3H), 5.92 (dd, J=2 Hz, 2 Hz, 2H), 6.72(d, J=8 Hz, 1H), 6.80-6.90 (m, 3H), 7.04 (d, J=2 Hz, 1H), 7.30 (d, J=9Hz, 2H).

EXAMPLE 37trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-hexynyl)-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 4, 200 mg. of the puretrans,trans isomer, the compound resulting from Example 6A was reactedwith 109 mg of 1-bromo-2-hexyne, prepared by the method described inPerkin I, 2004 (1987), for 1 hour at 55° C., to give 226 mg of theintermediate ester. The ester was hydrolyzed using NaOH in ethanol-waterfor 3 hours at room temperature to give 175 mg of the title compound. ¹HNMR (CDCl₃, 300 MHz) δ 1.00(t, J=7 Hz, 3H), 1.54 (m, 2H), 2.14-2.22 (m,2H), 2.96 (dd, J=7 Hz, 13 Hz, 1H), 3.07 (dd, J=18 Hz, 2 Hz, 1H), 3.15(dd, J=9 Hz, 2Hz, 1H), 3.26 (t, J=9Hz, 1H), 3.36 (dd, J=18 Hz, 2 Hz,1H), 3.47-3.55 (m, 1H), 3.79 (s, 3H), 3.88 (d, J=9 Hz, 1H), 5.95 (s,2H), 6.72 (d, J=8 Hz, 1H), 6.80-6.88 (m, 3H), 7.03 (d, J=2 Hz, 1H), 7.22(d, J=9 Hz, 2H).

EXAMPLE 38trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-cyclopropylmethyl-N-propylaminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

The title compound was prepared using the procedures described inExample 1. m.p. 167-169° C. Rotational isomers were seen in the NMR. ¹HNMR (CDCl₃, 300 MHz) δ −0.1 (m), 0.05 (m), 0.12-0.25 (m), 0.32-0.51 (m),0.67 and 0.74 (2 triplets, 3H), 0.90-1.00 (m), 1.20-1.55 (m), 2.72 (d,J=13 Hz, 1H), 2.85-3.29 (m, 4H), 3.30-3.50 (m, 3H), 3.52-3.62 (m, 1H),3.65-3.73 (2 doublets, J=10 Hz, 2 Hz, 1H), 3.78 (s, 3H), 5.95 (2singlets, 2H), 6.72 (2 doublets, 2H), 6.80-6.90 (m, 3H), 7.00 and 7.05(2 doublets, J=9 Hz, 2H).

EXAMPLE 39trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-pentylaminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

The title compound was prepared as an amorphous solid using theprocedures described in Example 1. Rotational isomers were seen in theNMR. ¹H NMR (CDCl₃, 300 MHz) δ 0.85 (t, J=7 Hz, 3H), 1.00-1.08 (m),1.13-1.32 (m), 1.35-1,50 (m), 2.72-2.82 (2 doublets, J=13 Hz, 1H), 2.83and 2.86 (2 singlets, 3H), 2.92-3.20 (m, 3H), 3.22-3.45 (m, 3H),3.52-3.62 (m, 1H), 3.72 (2 doublets, 1H), 3.75 and 3.76 (2 singlets,3H), 5.92 (2 singlets, 2H), 6.72 (d, J=8 Hz, 1H), 6.80-6.87 (m, 3H),7.03 (2 doublets, J=2 Hz, 1H), 7.30 (d, J=9 Hz, 2H).

EXAMPLE 40trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-diisobutylaminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

The title compound was prepared using the procedures described inExample 1. m.p. 141-143° C. ¹H NMR (CDCl₃,300 MHz) δ 0.54 (d, J=7 Hz,3H), 0.70-0.90 (3 doublets, J=7 Hz, 9H), 1.60-1.75 (m, 1H), 1.90-2.02(m, 1H), 2.67 (d, J=13 Hz, 1H), 2.70 (d, J=13 Hz, 1H), 2.84 (dd, J=6 Hz,15 Hz, 1H), 2.96-3.06 (m, 2H), 3.20 (dd, J=9 Hz, 15 Hz, 1H), 3.35 (dd,J=2 Hz, 10 Hz, 1H), 3.44-3.60 (m, 4H), 3.70 (d, J=9 Hz, 1H), 3.79 (s,3H), 5.94 (dd, J=2 Hz, 2 Hz, 2H), 6.72 (d, J=9 Hz, 1H), 6.82-6.90 (m,3H), 7.03 (d, J=2 Hz, 1H), 7.31 (d, J=9 Hz, 2H).

EXAMPLE 41trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-(2-proynyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

The title compound was prepared as an amorphous solid using theprocedures described in Example 1. Rotational isomers were seen in theNMR. ¹H NMR (CDCl₃, 300 MHz) δ 2.09 and 2.32 (2 triplets, J=2 Hz, 1H),2.80-3.10 (m, 3H), 2.90 and 2.99 (2 singlets, 3H), 3.35-3.50 (m, 2H),3.52-3.62 (m, 1H), 3.78 (s, 3H), 4.03 (d, J=13 Hz, 1H), 4.00-4.30 (m,3H), 5.93 (s, 2H), 6.72 (2 doublets, J=8 Hz, 1H), 6.80-6.90 (m, 3H),7.02 and 7.11 (2 doublets, J=2 Hz, 1H), 7.30 (2 doublets, J=9 Hz, 2H).

EXAMPLE 42trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-(n-hexyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

The title compound was prepared as an amorphous solid using theprocedures described in Example 1. ¹H NMR (CDCl₃, 300 MHz) δ 0.85 (2triplets, J=7 Hz, 3H), 1.00-1.50 (m, 8H), 2.72-2.82 (2 doublets, J=13Hz, 1H), 2.81 and 2.86 (2 singlets, 3H), 2.92-3.20 (m, 3H), 3.22-3.45(m, 3H), 3.52-3.62 (m, 1H), 3.72 (2 doublets, 1H), 3.75 and 3.76 (2singlets 3H), 5.94 (2 singlets, 2H), 6.72 (d, J=8 Hz, 1H), 6.80-6.87 (m,3H), 7.03 (2 doublets, J=2 Hz, 1H), 7.30 (d, J=9 Hz, 1H).

EXAMPLE 43trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminoarbonylmethyl)-pyrrolidine-3-carboxylicAcid

The title compound was prepared using the procedures described inExample 1. m.p. 123-125° C. ¹H NMR (CDCl₃, 300 MHz) 5 0.79 (t, J=7 Hz,3H), 0.85 (t, J=7 Hz, 3H), 1.00-1.50 (m, 8H), 2.74 (d, J=13 Hz, 1H),2.90-3.09 (m, 4H), 3.23-3.50 (m, 3H), 3.38 (d, J=13 Hz, 1H), 3.52-3.62(m, 1H), 3.75 (d, J=10 Hz, 1H), 3.78 (s, 3H), 5.93 (dd, J=2 Hz, 4 Hz),6.71 (d, J=8 Hz, 1H), 6.81-6.89 (m, 3H), 7.03 (d, J=2 Hz, 1H), 7.30 (d,J=9 Hz, 2H). MS (DCl/NH₃) m/e 511 (M+H)⁺. Anal calcd for C₂₉H₃₈N₂O₆: C,68.21; H, 7.50; N, 5.49. Found: C, 68.07; H, 7.47; N, 5.40.

EXAMPLE 44trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-diethylaminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

The title compound was prepared using the procedures described inExample 1. m.p. 132-134° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.98 (t, J=7 Hz,3H), 1.06 (t, J=7 Hz, 3H), 2.78 (d, J=13 Hz, 1H), 2.95-3.20 (m, 4H),3.30-3.50 (m, 4H), 3.55-3.65 (m, 1H), 3.76 (d, J=12 Hz, 1H), 3.79 (s,3H), 5.93 (s, 2H), 6.72 (d, J=8 Hz, 1H), 6.80-6.90 (m, 3H), 7.02 (d, J=2Hz, 1 H), 7.32 (d, J=9 Hz, 2H).

EXAMPLE 45trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

The title compound was prepared as an amorphous solid using theprocedures described in Example 1. ¹H NMR (CD₃OD, 300 MHz) δ 2.75-2.85(m, 2H), 3.05-3.13 (m, 1H), 3.18 (s, 3H), 3.40-3.58 (m, 2H), 3.78 (s,3H), 3.88 (d, J=12 Hz, 1H), 5.92 (s, 2H), 6.72 (d, J=8 Hz, 1H),6.75-6.85 (m, 3H), 7.00-7.12 (m, 5H), 7.82-7.92 (m, 3H).

EXAMPLE 46trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-cyclohexylaminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

The title compound was prepared as an amorphous solid using theprocedures described in Example 1. Rotational isomers were seen in theNMR. ¹H NMR (CD₃OD, 300 MHz) δ 1.00-1.85 (m, 10H), 2.72 and 2.78 (2singlets, 3H), 2.75-2.82 (2 doublets, J=12 Hz, 1H), 2.96-3.22 (m, 3H),3.40-3.65 (m, 3H), 3.68 and 3.82 (2 doublets, J=10 Hz, 1H), 3.77 and3.78 (2 singlets, 3H), 5.92 (s, 2H), 6.72 (2 doublets, J=8 Hz, 1H),6.82-6.88 (m, 3H), 7.02 (2 doublets, J=2 Hz, 1H), 7.30-7.40 (2 doublets,J=9 Hz, 2H).

EXAMPLE 47trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-proyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

The title compound was prepared using the procedures described inExample 1. m.p. 170-172° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.69 (t, J=7 Hz,3H), 0.85 (t, J=7 Hz, 3H), 1.20-1.55 (m, 4H), 2.72 (d, J=13 Hz, 1H),2.90-3.10 (m, 4H), 3.25-3.47 (m, 4H), 3.35-3.62 (m, 1H), 3.72 (d, J=9Hz, 1H), 3.79 (s, 3H), 5.94 (s, 2H), 6.72 (d, d, J=8 Hz, 1H), 6.80-6.90(m, 3H), 7.02 (d, J=2 Hz, 1H), 7.30 (d, J=9 Hz, 2H).

EXAMPLE 48trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-isobutylaminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

The title compound was prepared as an amorphous solid using theprocedures described in Example 1. Rotational isomers were seen in theNMR. ¹H NMR (CD₃OD, 300 MHz) δ 0.65-0.85 (4 doublets, J=7 Hz, 6H),1.75-1.95 (m, 1H), 2.80 and 2.90 (2 singlets, 3H), 2.90-3.10 (m, 4H),3.10-3.65 (m, 4H), 3.74 9S, 3H), 3.81 and 3,88 (2 doublets, J=10 Hz,1H), 5.93 (s, 2H), 6.72 (d, J=8 Hz, 1H), 6.80-6.90 (m, 3H), 7.02 (2doublets, J=2 Hz, 1H), 7.80-7.90 (2 doublets, J=9 Hz, 2H).

EXAMPLE 49 Alternate Prepration of Ethyl2-(4-Methoxybenzoyl)-4-nitromethyl-3-(1,3-benzodioxole-5-yl)butyrateEXAMPLE 49A E-2-(3,4-Methylenedioxyphenyl)-1-nitroethene

To a stirred solution of piperonal (75 g, 500 mmol) in methanol (120 mL)at 10° C. was added nitromethane (27.1 mL, 500 mmol, 1 eq) followed bythe dropwise addition of sodium hydroxide (21 g, 525 mmol, 1.05 eq) insufficient water to achieve a total volume of 50 mL while maintainingthe temperature between 10-15° C. The reaction mixture became cloudy,turning to a thick paste. The mixture was stirred for 30 minutes uponcompletion of the addition, and the mixture was then diluted withice-water (˜350 mL) maintaining the temperature below 5° C., untilsolution was achieved. The resultant solution was poured in a narrowstream (such that it just failed to break into drops) into a rapidlystirred solution of 36% hydrochloric acid (100 mL) in water (150 mL). Ayellow solid precipitated (nitrostyrene), and this was collected byfiltration, washed with water (1.5 L) until the filtrate was neutral.The filter cake was air dried and then recrystallized from hot ethanol(3 L) to yield E-2-(3,4-methylenedioxy)-nitrostyrene as yellow needles(53 g, 55%). ¹H NMR (300 MHz, CDCl₃) δ 7.94 (1H, d, J=13.5 Hz, 7.47 (1H,d, J=13.5 Hz), 7.09 (1H, dd, J=7.5&2 Hz), 7.01 (1H, d, J=2 Hz), 6.87(1H, d, J=7.5 Hz), 6.06 (2H, s). MS (DCl/NH₃) m/e 194 (M+H)⁺, 211(M+H+NH₃)⁺.

EXAMPLE 49B Ethyl2-(4-methoxyphenyl)oxo-4-nitro-3-(3,4-methylenedioxyphenyl)butyrate

To a stirred solution of the nitrostyrene resulting from Example 49A(14.17 g, 73.34 mmol, 1.2 eq) in a mixture of propan-2-ol (75 mL) andtetrahydrofuran (175 mL) at room temperature was added successively asolution of ethyl (4-methoxybenzoyl)acetate (11.5 g, 51.7 mmol) in THF(50 mL) followed by 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) (0.45 mL,3.0 mmol, 0.05 eq). The resultant mixture was stirred at roomtemperature for 1 hour, then additional DBU (0.45 mL, 3.0 mmol, 0.05 eq)was added. The mixture was stirred a further 1 hour, then the volatileswere removed in vacua and the residue purified by flash chromatographyon 500 g silica gel, eluting with 20% ethyl acetate-hexanes changing to25% ethyl acetate-hexanes as the product eluted. The solvents wereremoved in vacuo to yield the nitroketoester (19.36 g, 76%) as a viscousoil. Diastereomers were seen in the NMR. ¹H NMR (300 MHz, CDC₃) δ 8.06(2H, d, J=9 Hz), 7.89 (2H, d, J=9 Hz), 6.96 (2H, d, J=9 Hz), 6.91 (2H,d, J=9 Hz), 6.77 (1H, dd, J=9 Hz,3 Hz), 6.73 (1H, d, J=9 Hz), 6.65 (1H,d, J=3 Hz), 5.95 (2H, s), 5.89 (1H, d, J=4 Hz), 5.88 (1H, d, J=4 Hz),4.90-4.60 (3H, m), 4.39 (1H, m), 4.18 (2H, q, J=7 Hz), 3.94 (2H, m),3.80 (3H, s), 3.78 (3H, s), 1.19 (3H, t, J=7 Hz), 0.99 (3H, t, J=7Hz),MS (DCl/NH₃) m/e 416 (M+H)⁺, 433 (M+H+NH₃)⁺.

EXAMPLE 50trans,trans-2-(4-Methogyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(t-butyloxycarbonylmethyl)-pyrrolidine-3-carboxylicAcid

To a stirred solution of the compound resulting from Example 1C (100 mg,0.27 mmol) in acetonitrile (2 mL) was added successivelydiisopropylethylamine (70 μL, 0.40 mmol, 1.5 eq) and t-butylbromoacetate (48 μL, 0.29 mmol, 1.1 eq). The mixture was stirred 2hours, then the solvent was removed in vacuo to yield the crude diester.To a stirred solution of the diester in ethanol (1 mL) at roomtemperature was added 50% w/w sodium hydroxide (300 mg, 3.75mmol) inwater. The mixture was stirred 2 hours, then the volatiles were removedin vacuo. The residue was dissolved in water (5 mL), and the solutionwas washed with ether. The aqueous phase was acidified with acetic acid(300 μL), and then extracted with ethyl acetate (2×). The combinedorganic extracts were dried (Na₂SO₄), filtered, and concentrated toyield the title compound (74 mg, 60%) as a white solid. ¹H NMR (300 MHz,CDCl₃) δ 7.36 (2H, d, J=8 Hz), 7.13 (1H, d, J=3 Hz), 6.90 (1H, dt, J=3Hz, 8 Hz), 6.88 (2H, d, J=8 Hz), 6.76 (1H, d, J=8 Hz), 5.96 (2H, s),3.96 (1H, d, J=9 Hz), 3.81 (3H, s), 3.58 (1H, ddd, J=12, 10 Hz,3 Hz),3.52 (1H, dd, J=9 Hz,3 Hz), 3.32 (1H, d, J=17 Hz), 3.08 (1H, t, J=10Hz), 2.92 (1H, dd, J=9 Hz,7 Hz), 2.83 (1H, d, J=17 Hz). MS (DCl/NH₃) m/e456 (M+H)⁺. Anal calc for C₂₉H₂₉NO₇. 0.3 H₂O: C, 65.07; H, 6.48; N,3.04. Found: C, 65.02; H, 6.42; N, 2.93.

EXAMPLE 51trans,trans-2-(4-Methoxyphenyl)-4-(1-naphthyl)-1-(N-methyl-N-propyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting naphthalene-1-carboxaldehyde for piperonyl inExample 49A. Rotational isomers are seen in the- NMR. ¹H NMR (300 MHz,CDCl₃) δ 8.29 (1H, bd, J=8 Hz), 7.86 (2H, d, J=8 Hz),7.75 (1H, d, J=8Hz), 7.49 (3H, m), 7.34 (2H, dd, J=3 Hz,9 Hz), 6.83 (2H, dd, J=9 Hz,2Hz), 4.50 (1H, m), 3.94 (1H, dd, J=9 Hz,2 Hz), 3.78 (3H, s), 3.65 1H,m), 3.49 (1H, d, J=14 Hz), 3.40-2.93 (5H, m), 2.91, 2.83 (3H, s), 1.482H, sept, J=7 Hz), 0.83, 0.77 (3H, t, J=7 Hz). MS (DCl/NH₃) m/e 461M+H)⁺. Anal calcd for C₂₉H₂₉NO₇.0.5 HOAc: C, 71.00; H, 6.99; N, 5.71.Found: C, 70.95; H, 7.00; N, 5.46.

EXAMPLE 52trans,trans-2-(4-Methoxyphenyl)-4-(2,3-dihydrobenzofuran-5-yl)-1-(N-methyl-N-propyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid EXAMPLE 52A 2,3-Dihydrobenzofuran-5-carboxaldehyde

To a stirred solution of α,α-dichloromethyl methyl ether (2.15 g, 19mmol, 1.35 eq) in methylene chloride (30 mL) at −40° C. was addedsuccessively stannic chloride (1.65 g, 17 mmol, 1.2 eq) and 15 minuteslater, a solution of 2,3-dihydrobenzofuran (1.68 g, 14 mmol) in CH₂Cl₂(5 mL) maintaining the temperature at or below −35° C. The mixture waswarmed to 0° C., stirred 1 hour, then poured into ice-water, and stirreda further 30 minutes. The mixture was diluted with ether, and the phasesseparated. The organic phase was concentrated in vacuo, and the residuepurified by vacuum distillation to yield the title compound (1.25 g,60%) as a colorless liquid. b.p. 119-121° C. at 0.3 mm Hg.

EXAMPLE 52Btrans,trans-2-(4-Methoxyphenyl)-4-(2,3-dihydrobenzofuran-5-yl)-1-(N-methyl-N-propyl)aminocarbonylmethyl)-pyrrblidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting the compound resulting from Example 52A forpiperonal in Example 49A. Rotational isomers are seen in the NMR. ¹H NMR(300 MHz, CDCl₃) δ 7.33 (1H, d, J=8 Hz), 7.28 (1H, m), 7.19 (1H, m),6.87 (1H, d, J=8 Hz), 6.73 (1H, d, J=8 Hz), 4.56 (1H, t, J=8 Hz), 3.83(1H, d, J=10 Hz), 3.80 (3H, s), 3.63 (1H, m), 3.4-3.0 (9H, m), 2.87,2.84 (3H, s), 1.51 (2H, septet, J=7 Hz), 0.88, 0.78 (3H, t, J=7 Hz). MS(DCl/NH₃) m/e 453 (M+H)⁺. Anal calc for C₂₆H₃₂N₂O₅.0.25 H₂O: C, 68.33;H, 7.17; N, 6.13. Found: C, 68.60; H, 6.88; N, 5.80.

EXAMPLE 53trans,trans-2,4-Bis(4-methoxyphenyl)-1-(N-methyl-N-propyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting 4-methoxybenzaldehyde for piperonal in Example49A. Rotational isomers are seen in the NMR. ¹H NMR (300 MHz, CDCl₃) δ7.37 (2H, d, J=7.5 Hz), 7.32 (2H, d, J=7.5 Hz), 6.86 (4H, m), 3.83 (1H,m), 3.81 (3H, s), 3.79 (3H, s), 3.64 (1H, m), 3.48-2.97 (6H, m), 2.87,2.83 (3H, s), 2.85 (1H, m), 1.45 (2H, m), 0.84, 0.74 (3H, t, J=7.5 Hz).MS (DCl/NH₃) m/e 441 (M+H)⁺. Anal calc for C₂₅H₃₂N₂O₅.0.5 H₂O: C, 66.80;H, 7.40; N, 6.23. Found: C, 67.15; H, 7.31; N, 6.00.

EXAMPLE 54trans,trans-2-(4-Methoxyphenyl)-4-(3,4-dimethoxyphenyl)-1-(N-methyl-N-propyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described -in Examples1 and 49 substituting 3,4-dimethoxybenzaldehyde for piperonal in Example49A. Rotational isomers are seen in the NMR. ¹H NMR (300 MHz, CDCl₃) δ7.33 (2H, d, J=7.5 Hz), 7.07 (1H, d, J=2.0 Hz), 6.98 (1H, m), 6.85 (1 H,d, 7.5 Hz), 6.82 (2H, d, 7.5 Hz), 3.91 (3H, s), 3.86 (3H, s), 3.83 (1H,m), 3.79 (3H, s), 3.64 (1H, m), 3.50-2.95 (6H, m), 2.87 (1H, m), 2.85,2.83 (3H, s), 1.45 (2H, m), 0.84, 0.74 (3H, t, J=7.5 Hz). MS (DCl/NH₃)m/e 471 (M+H)⁺. Anal calc for C₂₆H₃₄N₂O₆.0.5 H₂O: C, 65.12; H, 7.36; N,5.84. Found: C, 65.22; H, 7.27; N, 5.59.

EXAMPLE 55trans,trans-2-(4-Methoxyphenyl)-4-(3-methoxyphenyl)-1-(N-methyl-N-propyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting 3-methoxybenzaldehyde for piperonal in Example49A. Rotational isomers are seen in the NMR. ¹H NMR (300 MHz, CDCl₃) δ7.33 (2H, d, J=7.5 Hz), 7.24 (1H, t, J=7.5 Hz), 7.05 (2H, m), 6.85 (2H,dd, J=7.5&2 Hz), 6.76 (1H, m), 3.83 (1H, m), 3.81 (3H, s), 3.79 (3H, s),3.64 (1H, m), 3.48-2.97 (6H, m), 2.87, 2.83 (3H, s), 2.85 (1H, m), 1.45(2H, m), 0.84, 0.74 (3H, t, J=7.5 Hz). MS (DCl/NH₃) m/e 441 (M+H)⁺. Analcalc for C₂₅H₃₂N₂O₅.0.5 H₂O: C, 66.80; H, 7.40; N, 6.23. Found: C,66.76; H, 7.36; N, 6.05.

EXAMPLE 56trans,trans-2-(4-Methoxyphenyl)-4-(2-naphthyl)-1-(N-methyl-N-propyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting naphthylene-2-carboxaldehyde for piperonal inExample 49A. Rotational isomers are seen in the NMR. ¹H NMR (300 MHz,CDCl₃) δ 7.82 (4H, m), 7.69 (1H, m), 7.47 (2H, m), 7.37 (2H, dd, J=7.5&2Hz), 6.85 (2H, dd, J=7.5&2 Hz), 3.90 (1H, d, J=8 Hz), 3.78 (3H, s), 3.57(1H, m), 3.52-2.97 (6H, m), 2.93, 2.85 (3H, s), 2.90 (1H, m), 1.52 (2H,m), 0.86, 0.76 (3H, t, J=7.5 Hz). MS (DCl/NH₃) m/e 461 (M+H)⁺. Anal calcfor C₂₈H₃₂N₂O₄.0.5 H₂O: C, 71.62; H, 7.08; N, 5.97. Found: C, 71.58; H,7.11; N, 6.01.

EXAMPLE 57trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(ethylsulfinyl)ethyl)-pyrrolidine-3-carboxylicAcid

To the compound resulting from Example 1C (100 mg, 0.27 mmol) and2-chloroethyl ethyl sulfide (67.5 mg, 0.5 mmol, 2 equivalents) dissolvedin 6 mL of acetonitrile was added 10 mg of Kl and 0.5 mL ofdiisopropylethylamine. The mixture was refluxed for 4 hours and thenconcentrated in vacuo. The residue obtained was purified by flashchromatography on silica gel eluting with 4:1 hexane-ethyl acetate toafford 93 mg (75%) of the ethylthioethyl compound.

To the sulfide (90 mg, 0.2 mmol) dissolved in 5 mL of CH₂Cl₂ in an icebath was added 68 mg of 3-chloroperoxybenzoic acid. The mixture wasstirred for 40 minutes in the ice bath and for 3 hours at roomtemperature. A 10% solution of sodium hydroxide (2 mL) was added, andthe mixture was extracted with EtOAc (2×50 mL). The combined organicextracts were washed with water and brine, dried over sodium sulfate andconcentrated in vacuo. The residue obtained was chromatographed onsilica gel eluting with EtOAc and 10% MeOH in CH₂Cl₂ to afford thesulfoxide (62 mg, 65%).

The ethyl ester was hydrolyzed by the procedure described in Example 1Dto afford the title compound as a diastereomeric mixture. m.p. 61-63° C.MS (DCl/NH₃) m/e 446 (M+H)⁺. ¹H NMR (CDCl₃, 300 MHz) δ 1.25, 1.32 (t,J=9 Hz, 3H), 2.45-2.75 (m, 4H), 2.84-2.96 (m, 3H), 3.02-3.08 (m, 1H),3.32, 3.36 (d, J=3 Hz, 1H), 3.47-3.58 (m, 2H), 3.65, 3.68 (d, J=7.5 Hz,1H), 3.76, 3.80 (s, 3H), 5.94 (s, 2H), 6.72 (d, J=7.5Hz, 1H), 3.84-3.89(m, 3H), 7.02 (d, J=6 Hz, 1H), 7.30, 7.34 (d, J=7.5 Hz, 2H).

EXAMPLE 58trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(isopropylsulfonylamino)ethyl)-pyrrolidine-3-carboxylicAcid

To 2-bromoethylamine hydrobromide (1 mmol) suspended in anhydrous CH₃CNwas added 1 equivalent of Et₃N. The mixture was stirred for 30 minutesand then 1 equivalent of isopropyl sulfonyl chloride and 1 equivalent ofEt₃N were added. The resulting mixture was stirred for 2 hours at roomtemperature and then added to a solution of the compound resulting fromExample 1C (185 mg, 0.5 mmol) in 3 mL of CH₃CN. The mixture was warmedat 50-60° C. for 2 hours, cooled to room temperature, treated with waterand extracted with EtOAc. The combined organic extracts were washed withwater and brine, dried and concentrated in vacuo. The residue obtainedwas chromatographed on silica gel eluting with 3:2 hexane-EtOAc to give195 mg (75%) of the ethyl ester. The ethyl ester (160 mg, 0.31 mmol) washydrolyzed by the procedure described in Example 1D to afford the titlecompound (133 mg, 88%). m.p. 94-96° C. ¹H NMR (CD₃OD, 300 MHz) δ 1.26(d, J=6 Hz, 6H), 1.97 (s, 1 H), 2.38 (m, 1H), 2.77 (m, 1H), 2.88 (t, J=9Hz, 1H), 3.04 (m, 1H), 3.14 (t, J=7.5 Hz, 2H), 3.35 (m, 2H), 3.46 (m,1H), 3.58 (m, 1H), 3.78 (s, 3H), 5.92 (s, 2H), 6.74 (d, J=9Hz, 1H), 6.86(dd, J=9Hz,3Hz, 1H), 6.92 (d, J=9Hz, 2H), 7.00 (d, J=3Hz, 1H), 7.36 (d,J=9 Hz, 2H). MS (DCl/NH₃) m/e (M+H)⁺.

EXAMPLE 59trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(isobutoxy)ethyl)-pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Example1D from the compound resulting from Example 1C and 2-(isobutoxy)ethylbromide. m.p. 68-70° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.88 (d, J=6 Hz, 6H),1.82 (quintet, J=6 Hz, 1H), 2.22 (m, 2H), 2.72-2.79 (m, 1H), 2.86-2.95(m, 2H), 3.13 (d, J=6 Hz, 2H), 3.45-3.56 (m, 4H), 3.68 (d, J=9 Hz, 1H),3.79 (s, 3H), 5.94 (s, 2H), 6.72 (d, J=7.5 Hz, 1H), 6.85 (dd, J=9 Hz,7.5 Hz, 3H), 7.08 (s, 1H), 7.34 (d, J=9 Hz, 2H). MS (DCl/NH₃) m/e 442(M+H)⁺.

EXAMPLE 60trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(butylsulfonyl)-pyrrolidine-3-carboxylicAcid

To 100 mg (0.271 mmol) of the compound resulting from Example 1Cdissolved in 10 mL of THF was added 1-butanesulfonyl chloride (46.7 mg,1.1 equivalents) and diisopropylethylamine (53 mg, 1.5 equivalents). Theresulting mixture was stirred for 2.5 hours at room temperature and thenthe solvent evaporated. The crude product was purified by flashchromatography on silica gel eluting with 3:2 hexane-EtOAc to afford 120mg (90%) of the ethyl ester.

The ester (120 mg, 0.244 mmol) was dissolved in 1 mL of EtOH, and asolution of 100 mg of NaOH in 1 mL of water was added. The mixture wasstirred for 3 hours at room temperature and then concentrated underreduced pressure. Water (5 mL) was added and the solution was washedwith ether to remove any unhydrolyzed trans-cis isomer. The aqueoussolution was acidified to pH-6 with acetic acid and then extracted withEtOAc (2×50 mL). The combined organic extracts were washed with brine,dried over sodium sulfate and concentrated under reduced pressure toafford the pure title compound (60 mg, 53%) as a white solid. m.p.67-69° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.82 (t, J=7.5 Hz, 3H), 1.20-1.33(m, 2H), 1.58-1.68 (m, 2H), 2.48-2.69 (m, 2H), 3.28 (dd, J=9 Hz, 1H),3.49 (t, J=12 Hz, 1H), 3.65 (dd, J=12 Hz, 1H), 3.82 (s, 3H), 4.32 (dd,J=12 Hz, 1H), 5.17 (d, J=9 Hz, 2H), 5.95 (s, 2H), 6.70-6.78 (m, 3H),6.92 (d, J=9 Hz, 2H), 7.35 (d, J=9 Hz, 2H). MS (DCl/NH₃) m/e 462 (M+H)⁺.

EXAMPLE 61trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-methyl-N-isopropylcarbonylamino)ethyl)-pyrrolidine-3-carboxylicAcid EXAMPLE 61Atrans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-bromoethyl)-pyrrolidine-3-carboxylicAcid Ethyl Ester

To the mixture of cis,trans and trans,trans pyrrolidines resulting fromExample 1C (400 mg) dissolved in 9 mL of 1,2-dibromoethane was added 0.7mL of diisopropylethylamine and 30 mg of sodium iodide. The resultantmixture was heated at 100° C. for 1 hour, and then the solvents wereremoved in vacuo. The residue was taken up in EtOAc and washedsequentially with water and brine, dried and concentrated under reducedpressure. The crude product was purified by flash chromatography onsilica gel eluting with 4:1 hexane-EtOAc to give 470 mg of the titleproduct.

EXAMPLE 61Btrans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(methylamino)ethyl)-pyrrolidine-3-carboxylicAcid Ethyl Ester

To the compound resulting from Example 61A (450 mg) dissolved in 10 mLof EtOH was added 0.5 mL of 40% aqueous methylamine and 50 mg of sodiumiodide. The mixture was heated at 80° C. for 1 hour, and then thesolvents were removed in vacuo. The residue was taken up in EtOAc andwashed sequentially with water and brine, dried and concentrated invacuo. The resultant product was carried on without furtherpurification.

EXAMPLE 61Ctrans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-methyl-N-isobutyrylamino)ethyl)-pyrrolidine-3-carboxylicAcid

To the compound resulting from Example 61B (˜150 mg) dissolved in 5 mLof 1,2-dichloroethane was added 0.3 mL of diisopropylethylamine. Thesolution was cooled to −40° C, isobutyryl chloride (0.17 mL) was added,the bath was removed, and the solution was allowed to warm to ambienttemperature and stirred for 15 hours. The solvent was removed in vacuo;the residue was taken up in EtOAc and washed sequentially with 1:1sodium bicarbonate solution/water and brine, dried and concentrated invacuo. The product was purified by flash chromatography on silica geleluting with a gradient 1:1 EtOAc-hexanes going to EtOAc and finallyusing 10% MeOH-EtOAc.

The ester was dissolved in 1.5 mL of EtOH; 0.75 mL of a 17% aqueous NaOHsolution was added, and the resultant mixture was stirred at ambienttemperature for 3 hours. The solvents were removed in vacuo; the residuewas taken up in water and washed with ether. The aqueous phase wasacidified with 1 N H₃PO₄ to pH 3 and extracted twice with ether. Thecombined organic extracts were washed with brine and dried over Na₂SO₄.The solvents were removed in vacuo to provide 82 mg of the titlecompound as a white foam. Rotamers were seen in the NMR. ¹H NMR (CDCl₃,300 MHz) of the major rotamer δ 1.06 (d, 3H, J=10 Hz), 1.12 (d, 3H, J=10Hz), 2.15 (m, 1H), 2.5-3.0 (m, 3H), 2.91 (s, 3H), 3.32 (m, 2H), 3.50 (m,2H), 3.65 (m, 2H), 3.77 (s, 3H), 5.92 (s, 2H), 6.73 (d, 1H, J=8 Hz),6.75-6.9 (m, 4H), 6.96 (d, 1H, J=2 Hz), 7.29 (m, 1H). MS (DCl/NH₃) m/z469 (M+H)⁺. Analysis calcd for C₂₆H₃₂N₂O₆.0.3 TFA: C, 63.55; H, 6.48; N,5.57. Found: C, 63.44; H, 6.71; N, 5.24.

EXAMPLE 62trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-methyl-N-propionylamino)ethyl)-pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Example61 substituting propionyl chloride for isobutyryl chloride in Example61C. ¹H NMR (CDCl₃, 300 MHz) of the major rotamer δ 1.13 (t, 3H, J=8Hz), 2.19 (m, 1H), 2.30 (m, 2H), 2.65-3.0 (m, 3H), 2.85 (s, 3H),3.25-3.4 (m, 2H), 3.5-3.7 (m, 3H), 3.79 (s, 3H), 5.92 (s, 2H), 6.74 (d,1H, J=8 Hz), 6.75-6.9 (m, 4H), 7.00 (bd s, 1H), 7.29 (bd s, 1H). MS(DCl/NH₃) m/z 455 (M+H)⁺. Analysis calcd for C₂₅H₃₀N₂O₆.1.0 H₂O: C,63.55; H, 6.83; N, 5.93 . Found: C, 63.55; H, 6.52; N, 5.73.

EXAMPLE 63trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-benzylaminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 1 the title compound wasprepared. ¹H NMR (CDC13, 300 MHz) of the major rotamer δ 2.79 .(s, 3H),2.8-3.2 (m, 2H), 3.48 (m, 2H), 3.61 (m, 2H), 3.77 (s, 3H), 3.78 (m, 1H),4.3-4.5 (m, 2H), 5.95 (d, 2H, J=2 Hz), 6.7-6.9 (m, 4H), 7.00 (m, 1H),7.15-7.35 (m, 7H). MS (FAB/NBA) m/z 503 (M+H)⁺. Anal calcd forC₂₉H₃₀N₂O₆. 0.5 H₂O: C, 68.36; H,5.74; N, 5.50. Found: C,68.41; H, 5.74;N, 5.36.

EXAMPLE 64trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-ethyl-N-butylaminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 1 the title compound wasprepared. ¹H NMR (CDCl₃, 300 MHz) of the major rotamer δ 0.88 (t, 3H,J=7 Hz), 1.06 (t, 3H, J=7 Hz), 1.27 (m, 2H), 1.45 (m, 2H), 2.8-3.6 (m,11H), 3.79 (s,3H), 3.80 (m, 1H), 5.92 (bd s, 2H), 6.75 (d, 1H, J=8 Hz),6.85 (d, 1H, J=8 Hz), 6.92 (d, 2H, J=8 Hz), 7.03 (s, 1H), 7.33 (d, 1H,J=8 Hz). MS (DCl/NH₃) m/z 483 (M+H)⁺. Anal calcd for C₂₇H₃4N₂O₆. 0.5HOAc: C, 65.61; H,7.08; N, 5.46. Found: C,65.51; H, 6.70; N, 5.66.

EXAMPLE 65trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl-1-(N-methyl-N-(2,2-dimethylpropylaminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 1 the title compound wasprepared. ¹H NMR (CDCl₃, 300 MHz) of the major rotamer δ 0.90 (s, 9H),2.8-3.1 (m, 4H), 2.94 (s, 3H), 3.3-3.5 (m, 3H), 3.61 (m, 1H), 3.80 (s,3H), 3.82 (m, 1H), 5.94 (bd s, 2H), 6.74 (d, 1H, J=8 Hz), 6.86 (d, 2H,J=8 Hz), 6.87 (m, 1H), 7.03 (d, 1H, J=2 Hz), 7.33 (d, 2H, J=8 Hz). MS(DCl/NH₃) m/z 483 (M+H)⁺.

EXAMPLE 66trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-methyl-N-butylsulfonylamino)ethyl)-pyrrolidine-3-carboxylicAcid

To the compound resulting from Example 61B (60 mg, 0.13 mmol) dissolvedin 5 mL of CH₃CN was added 0.2 mL of Et₃N and. 22 mg (0.143 mmol, 1.1equivalents) of 1-butanesulfonyl chloride. The mixture was stirred for 1hour at room temperature and then concentrated in vacuo. The crudeproduct was purified by column chromatography on silica gel eluting with1:1 EtOAc-hexane to yield 64 mg (90%) of the ester. Ester hydrolysis bythe procedure described in Example 1D afforded the title compound. m.p.64-66° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.92 (t, J=7.5 Hz, 3H), 1.39 (hexad,J=7.5 Hz, 2H), 1.68-1.76 (m, 2H), 2.16-2.25 (m, 1H), 2.72 (s, 3H),2.75-2.92 (m, 5H), 3.12-3.20 (m, 1H), 3.25-3.34 (m, 1H), 3.46-3.55 (m,2H), 3.65 (d, J=9 Hz, 1H), 3.78 (s, 3H), 5.53 (s, 2H), 6.72 (d, J=7.5Hz, 1H), 6.82 (dd, J=7.5 Hz,3 Hz, 1H), 6.86 (d, J=9Hz, 2H), 7.02 (d, J=3Hz, 1H), 7.34 (d, J=9 Hz, 2H). MS (DCl/NH₃) m/e 519 (M+H)⁺.

EXAMPLE 67trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-methyl-N-propylsulfonylamino)ethyl)-pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Example66 substituting 1-propanesulfonyl chloride for 1-butanesulfonylchloride. m.p. 69-70° C. ¹H NMR (CDCl₃, 300 MHz) δ 1.02 (t, J=7.5 Hz,3H), 1.78 (hexad, J=7.5 Hz, 2H), 2.18-2.26 (m, 1H), 2.72 (s, 3H),2.75-2.95 (m, 6H), 3.13-3.22 (m, 1H), 3.25-3.35 (m, 1H), 3.47-3.58 (m,2H), 3.66 (d, J=9 Hz, 1H), 3.80 (s, 3H), 5.96 (s, 2H), 6.74 (d, J=7.5Hz, 1H), 6.84 (d,d, J=7.5 Hz, 3 Hz, 1H), 6.87 (d, J=9 Hz, 2H), 7.04 (d,J=3 Hz, 1H), 7.43 (d, J=9 Hz, 2H). MS (DCl/NH₃) m/e 505 (M+H)⁺.

EXAMPLE 68trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(propylsulfonyl)ethyl)-pyrrolidine-3-carboxylicAcid

To 1-propanethiol (3.5 g, 46.05 mmol) dissolved in 10 mL of anhydrousTHF was added 632 mg (26.32 mmol) of NaH in portions under a nitrogenatmosphere. The mixture was heated at 60-70° C. for 1 hours. To thismixture was added the compound resulting from Example 61A (180 mg, 0.38mmol) in 2 mL THF. Heating was continued at 60-70° C. for an additional2 hours, and then the volatiles were removed under reduced pressure. Thecrude propylthioethyl adduct was purified by flash chromatography onsilica gel eluting with 3:2 hexane-EtOAc to give 170 mg (95%).

To a solution of 170 mg (0.36 mmol) of the sulfide and 93 mg (0.8 mmol)of N-methylmorpholine N-oxide (NMO) in a mixture of 20 mL of acetone and5 mL of H₂O was added a solution of osmium tetroxide (10 mg) in 0.3 mLof t-butanol. The resulting mixture was stirred overnight at roomtemperature and then concentrated under reduced pressure. The residuewas partitioned between EtOAc and H₂O. The organic phase was washed withbrine, dried over Na₂SO₄ and concentrated in vacuo. Flash chromatographyafforded 177 mg (98%) of the ethyl ester which was hydrolyzed by theprocedures described in Example 1D to afford the title compound. m.p.73-75° C. ¹H NMR (CDCl₃, 300 MHz) δ 1.04 (t, J=7.5 Hz, 3H), 1.78 (hexad,J=7.5 Hz, 2H), 2.59-2.66 (m, 1H), 2.84-3.08 (m, 7H), 3.43 (dd, J=9 Hz, 3Hz, 1H), 3.53-3.60 (m, 1H), 3.68 (d, J=9 Hz, 1H), 3.82 (s, 3H), 5.96 (s,2H), 6.75 (d, J=7.5 Hz, 1H), 6.82 (dd, J=7.5 Hz, 3 Hz, 1H), 6.88 (d, J=9Hz, 2H), 6.99 (d, J=3 Hz, 1H), 7.32 (d, J=9 Hz, 2H). MS (DCl/NH₃) m/e476 (M+H)⁺.

EXAMPLE 69trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-N-(trans-5-methylhex-2-enyl)-pyrrolidine-3-carboxylicAcid EXAMPLE 69A trans-5-Methylhex-2-enoic Acid Ethyl Ester

Oil dispersion sodium hydride (0.85 g) was washed with hexanes andsuspended in THF (20 mL), and the mixture was cooled in an ice bath to0° C. Diisopropyl(ethoxycarbonylmethyl) phosphonate (5.0 mL) was andsuspended in THF (20 mL), and the mixture was cooled in an ice bathIsovaleraldehyde (2.0 mL) in THF (5 mL) was added dropwise over fiveminutes. The ice bath was removed and the mixture stirred for 18 hoursat ambient temperature. Saturated ammonium chloride solution (50 mL) wasadded and the mixture extracted with diethyl ether (3×50 mL). The etherextracts were combined, dried with Na₂SO₄, and evaporated to was addedand the mixture extracted with diethyl ether (3×50 mL). The etherextracts were combined, dried with Na₂SO₄, and evaporated to colorlessoil (2.1 g).

EXAMPLE 69B trans-5-Methylhex-2-en-1-ol

The compound resulting from Example 69A (2.0 g) was dissolved in tolueneand cooled to 0° C. in an ice bath. Diisobutylaluminum hydride (1.5 Ntoluene, 20 mL) was added dropwise and the solution stirred at 0° C. fortwo hours. Citric acid solution (25 mL) was added very slowly to thecooled solution. The resulting mixture was stirred for 18 hours atambient temperature. Diethyl ether (50 mL) was added, the solids removedby filtration and washed with additional ether (2×25 mL). The filtratewas extracted with ether (2×25 mL). The ether extractions and washingswere combined, dried, and evaported to give a colorless oil which waspurified by flash chromatography on silica gel eluting with 25%EtOAc-hexanes. The title compound was isolated as a colorless oil (1.25g).

EXAMPLE 69C trans-1-Bromo-5-methylhex-2-ene

The compound resulting from Example 69B (1.0 g) was dissolved in diethylether and cooled to 0° C. in an ice bath. Phosphorus tribromide (2.5 g,0.87 mL) was added dropwise and the solution stirred at 0° C. for twohours. The solution was poured onto ice, the layers separated, and theaqueous layer extracted with additional ether (3×25 mL). The etherlayers were combined, dried, and evaporated to give a colorless oilwhich was used without further purification (0.95 g).

EXAMPLE 69D trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-N-(trans-5-methylhex-2-enyl)-pyrrolidine-3-carboxylic Acid

The title compound was synthesized using the methods detailed in Example1D but substituting the compound resulting from Example 69C for N-propylbromoacetamide. ¹H NMR (CDCl₃, 300 MHz) δ 0.84 (d, 6H, J=8 Hz), 1.57(heptet, 1H, J=8 Hz), 1.87 (t, 2H, J=6 Hz), 2.60 (dd, 1H, J=8 Hz, 14Hz), 2.86 (t, 1H, J=10 Hz), 2.96 (dd, 1H, J=8 Hz, 10 Hz), 3.20 (dd, 1H,J=5 Hz, 14 Hz), 3.29 (dd, 1H, J=3 Hz, 10 Hz), 3.50 (m, 1H), 3.70 (d, 1H,J=10 Hz), 3.78 (s, 3H), 5.47 (m, 2H), 5.93 (s, 2H), 6.71 (d, 1H, J=8Hz), 6.83 (d, 3H, J=9 Hz), 7.05 (s, 1H), 7.32 (d, 2H, J=9 Hz). MS(DCl/NH₃) m/e 438 (M+H)⁺. Anal calcd for C₂₆H₃₁NO₅: C, 71.37; H, 7.14;N, 3.20. Found: C, 71.16; H, 7.24; N, 3.17.

EXAMPLE 70trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-N-(trans-3,5-dimethylhex-2-enyl)-pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Example69 but substituting 4-methyl-2-pentanone for isovaleraldehyde in Example69A, which gave ˜7:1 mixture of trans/cis olefins. The crude product waspurified by preparative HPLC (Vydac μC18) eluting with a 10-70% gradientof CH₃CN in 0.1% TFA. The desired fractions were lyophilized to give theproduct (and its diastereomer) as a white solid. ¹H NMR of the major(trans) isomer: (CDCl₃, 300 MHz) δ 0.83 (d, 6H, J=8 Hz), 1.56 (s,3H),1.74 (m, 1H), 1.92 (d, 2H, J=6 Hz), 3.3-3.5 (m, 3H), 3.6-3.8 (m,4H),3.78 (s, 3H), 3.9-4.0 (m, 1H), 5.22 (m, 1H), 5.90 (d, 2H, J=12 Hz), 6.63(m, 1H), 6.78 (m, 3H), 6.95 (s, 1H), 7.45 (d, 3H, J=8 Hz). MS (DCl/NH₃)m/e 438 (M+H)⁺. Anal calcd for C₂₇H₃₃NO₅.1.0 TFA: C, 61.59; H, 6.06; N,2.48. Found: C, 61.36; H, 6.10; N, 2.34.

EXAMPLE 71trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(4-heptylcarbonylmethyl)-pyrrolidine-3-carboxylicAcid EXAMPLE 71A 1-Chloro-3-propyl-2-hexanone

To 2-propylpentanoic acid (156.6 μl, 1.00 mmol) dissolved in anhydrousdichloromethane (2 mL) was added DMF (3 μL, 4 mole %), and the solutionwas cooled to 0° C. under a nitrogen atmosphere. To the solution wasadded oxalyl chloride (94.3 μL, 1.08 mmol) dropwise over a few minutes.The reaction was stirred 18 hours while warming to ambient temperature.The mixture was cooled to 0° C. and excess ˜0.3 M ethereal diazomethanesolution was added. The reaction mixture was stirred 18 hours whilewarming to ambient temperature. The reaction mixture was washed with 1 Maqueous sodium carbonate solution (30 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas dissolved in ether (2 mL) and cooled to 0° C. under a nitrogenatmosphere. Hydrogen chloride as a 4 N solution in dioxane (275 μL, 1.10mmol) was added dropwise over a few minutes. The reaction was stirred 18hours while warming to ambient temperature. The reaction mixture wasconcentrated under reduced pressure and the residual oil was used in thenext step without further purification.

EXAMPLE 71B trans,trans-Ethyl2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(4-heptylcarbonylmethyl)-pyrrolidine-3-carboxylate

To the compound resulting from Example 71A (1.00 mmol, maximumtheoretical yield) was added a solution of the trans,trans ethylcarboxylate from Example 1C (295 mg, 0.80 mmol as a 50% solution intoluene), diisopropylethylamine (700 μL, 4.00 mmol) and acetonitrile (4mL). To the resulting solution was added sodium iodide (12 mg, 10 mole%), and the reaction mixture was stirred 18 hours under a nitrogenatmosphere at ambient temperature. Additional sodium iodide (24 mg, 20mole %) and acetonitrile (4 mL) were added, and the reaction mixture washeated at 45-50° C. with stirring for 18 hours. The reaction mixture wasconcentrated under reduced pressure, and the residue was chromatographedon silica gel eluting with 1:9 ethyl acetate-hexane to give 237 mg (46%)of the title compound as a yellow oil.

EXAMPLE 71Ctrans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(4-heptylcarbonylmethyl)-pyrrolidine-3-carboxylicAcid

To the compound resulting from Example 71B (231 mg, 0.4532 mmol)dissolved in ethanol (10 mL) was added a solution of lithium hydroxide(38 mg, 0.9065 mmol) in water (2.5 mL). The solution was stirred for 18hours under a nitrogen atmosphere, additional lithium hydroxide (19 mg,0.4532 mmol) in water (0.5 mL) was added, and stirring was continued 24hours. The reaction mixture was concentrated under reduced pressure toremove the ethanol, and the aqueous residue was diluted with water (45mL) and washed with ether (50 mL). The aqueous layer was neutralizedwith 1 N hydrochloric acid to cloudiness and then 10% aqueous citricacid was added to adjust the pH to ˜5. This solution was then extractedwith 10% ethanol in chloroform (4×25 mL). The combined organic extractswere dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by preparative TLC onsilica gel eluted with 1:1 ethyl acetate-hexane to give 86 mg (39%) ofthe title compound as an off white powder. ¹H NMR (CDCl₃, 300 MHz) δ0.73-0.97 (m, 6H), 1.03-1.33 (m, 6H), 1.36-1.58 (m, 2H), 2.46 (m, 1H),2.80-2.98 (m, 3H), 3.38-3.64 (m, 3H), 3.75-3.90 (m, 1H), 3.79 (s, 3H),5.94 (s, 2H), 6.75 (d, 1H), 6.86 (d, 2H), 6.92 (d, 1H), 7.12 (s, 1H),7.32 (d, 2H). MS (FAB) m/e 482 (M+H)⁺. Anal calcd for C₂₈H₃₅NO₆: C,69.83; H, 7.32; N, 2.91. Found: C, 69.57; H, 7.41; N, 2.73.

EXAMPLE 72trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(valerylmethyl)-pyrrolidine-3-carboxylicAcid EXAMPLE 72A 1-Chloro-2-hexanone

Using the procedure described in Example 71A and substituting pentanoicacid for 2-propylpentanoic acid afforded the title compound as an oilwhich was used in the next step without further purification.

EXAMPLE 72B trans,trans-Ethyl2-(4-methoxyphenyl)-4-(1,3-benzodioxole-5-yl)-1-(valerylmethyl)-pyrrolidine-3-carboxylate

Substituting the compound resulting from Example 72A for1-chloro-3-propyl-2-hexanone and using the procedure described inExample 71B, except deleting the first addition of sodium iodide,stirring 18 hours at ambient temperature and purifying by silica gelchromatography eluting with 3:17 ethyl acetate-hexane, the titlecompound 305 mg (65%) was obtained as a yellow oil.

EXAMPLE 72Ctrans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(valerylmethyl)-pyrrolidine-3-carboxylicAcid

By substituting the compound resulting from Example 72B fortrans,trans-Ethyl2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(4-heptylcarbonylmethyl)-pyrrolidine-3-carboxylateand using the procedure described in Example 71C, except only onesolution of lithium hydroxide (81.5 mg, 1.942 mmol) in water (3.5 mL)was added followed by stirring for 18 hours, the title compound 130 mg(46%) was obtained as an off white powder. ¹H NMR (CDCl₃, 300 MHz) δ0.87 (t, 3H), 1.26 (m, 2H), 1.49 (m, 2H), 2.37 (m, 2H), 2.79-2.98 (m,3H), 3.31-3.49 (m, 2H), 3.56 (m, 1H), 3.77, 3.79 (d,s, 4H), 5.94 (s,2H), 6.75 (d, 1H), 6.81-6.93 (m, 3H), 7.09 (d, 1H), 7.33 (d, 2H). MS(FAB) m/e 440 (M+H)⁺. Anal. calcd for C₂₅H₂₉NO₆: C, 68.32; H, 6.65; N,3.19. Found: C, 67.95; H, 6.64; N, 3.05.

EXAMPLE 73trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-(3,4-dimethoxybenzyl)-N-methylaminocarbonylmethyl)pyrrolidine-3-carboxylicAcid EXAMPLE 73A trans,trans- andcis,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-((3,4-dimethoxybenzyl)aminocarbonylmethyl)pyrrolidine-3-carboxylicAcid Ethyl Ester

Using the procedure of Example 1D, paragraph 1, substituting3,4-dimethoxybenzyl bromoacetamide for dipropyl bromoacetamide, thedesired product mixture was obtained as a white foam in 81% yield.

EXAMPLE 73B trans,trans- andcis,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-(3,4-dimethoxybenzyl)-N-methylaminocarbonylmethyl)pyrrolidine-3-carboxylicAcid Ethyl Ester

The resultant product from Example 73A (220 mg, 0.404 mmol) wasdissolved in 2 mL dry THF and added dropwise to a stirred, cooled (0°C.) suspension of sodium hydride (23 mg of a 60% by weight mineral oilsuspension, 16.5 mg, 0.69 mmol) in 0.2 mL THF, under an argonatmosphere. The resulting mixture was stirred at 0° C. for 1 hour, thenmethyl iodide (28 μL, 64 mg, 0.45 mmol) was added. The reaction mixturewas stirred at 0° C. for 45 minutes. TLC (Et₂O) indicated incompletereaction. An additional portion of methyl iodide (28 μL, 64 mg, 0.45mmol) and dry 1,3-dimethyl-3,4,5,6-tetrahydro-2(1l H)pyrimidinone (50μL, 0.41 mmol) were added. The reaction mixture was stirred at ambienttemperature for 2 days. The reaction was poured into 25 mL of 0.5 Maqueous citric acid and extracted with 2×25 mL EtOAc. The combinedorganic extracts were washed sequentially with 30 mL water and 30 mLbrine, then dried (Na₂SO₄), filtered and concentrated under reducedpressure to produce 270 mg of crude material. Flash chromatography onsilica gel eluting with Et₂O gave the title compounds as an inseparablemixture in 43% yield. ¹H NMR (CDCl₃, 300 MHz) δ 2.79 (s) and 2.81 (s),for the N—CH₃ signals. MS m/z 591 (M+H)⁺.

EXAMPLE 73Ctrans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-(3,4-dimethoxybenzyl)-N-methylaminocarbonylmethyl)pyrrolidine-3-carboxylicAcid

To the resultant compound from Example 73B (98 mg, 0.17 mmol) dissolvedin 1 mL EtOH and cooled to 0° C. was added a solution of lithiumhydroxide monohydroxide (17 mg, 0.41 mmol) in 0.5 mL H₂O. The resultingsolution was stirred under a nitrogen atmosphere for 16 hours. Thesolution was concentrated in vacuo, and the residue was partitionedbetween 15 mL H₂O and 15 mL Et₂O. The aqueous phase was extracted with 5mL Et₂O, then the aqueous phase was acidified with 10% aqueous citricacid. The acidic aqueous phase was saturated with NaCl and extractedwith 3×15 mL EtOAc. The EtOAc extracts were combined, dried (Na₂SO₄),then filtered and concentrated in vacuo to give 40 mg (42%) of the titlecompound as a white foam. ¹H NMR (CD₃O D, 300 MHz, two rotameric forms)δ 2.85 (s, 3H), 2.94-3.25 (br m, 3H), 3.35-3.70 (br m) and 3.64 (s, 4 Htotal), 3.70-3.97 (br. m), 3.74 (s), 3.76 (s), 3.78 (s), 3.79 (s), 3.81(s), and 4.03 (br d, J=14 Hz, 8H total), 4.43 (AB, 1H), 5.91 (s) and5.93 (s, 2H total), 6.50-6.60 (m, 1H), 6.67-7.02 (br m, 6H), 7.29 (br d)and 7.35 (br d, 2H total). HRMS calcd for C₃₁H₃₅N₂O₈ (M+H)⁺: 563.2393.Found: 563.2385.

EXAMPLE 74trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-(3,4-dimethoxybenzyl)aminocarbonylmethyl)pyrrolidine-3-carboxylicAcid

The procedure of Example 73C was used, with the substitution of theresultant compound from Example 73A for the resultant compound fromExample 73B, to provide the title compound. ¹H NMR (CD₃OD, 300 MHz) δ2.85 (d, J=16 Hz, 1H), 2.92 (br t, J=9 Hz, 1H), 2.98 (br t, J=10 Hz,1H), 3.32-3.39 (br m, 2H), 3.54-3.65 (br m, 1H), 3.67 (s, 3H), 3.78 (s,3H), 3.80 (s, 3H), 3.85 (d, J=10 Hz, 1H), 4.21 (d, J=15 Hz, 1H), 4.41(d, J=15 Hz, 1H), 5.91 (s, 2H), 6.67 (d, J=8 Hz, 1H), 6.75-6.95 (m, 7H),7.33-7.40 (m, 2H). HRMS calcd for C₃₀H₃₂N₂O₈ (M+H)⁺: 549.2237. Found:549.2224.

EXAMPLE 75 (2R,3R,4R)-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-((1R)-1-(N,N-dipropylaminocarbonyl)-1-butyl)pyrrolidine-3-carboxylic AcidEXAMPLE 75Atrans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-((1R)-1-(benzyloxycarbonyl)butyl)pyrrolidine-3-carboxylicAcid Ethyl Ester

The procedure of Fung, et. al., J. Med. Chem., 35(10): 1722-34 (1992)was adapted. The resultant compound from Example 6A (103 mg, 0.279 mmol)was dissolved in 0.7 mL of nitromethane and 0.7 mL of H₂O, and ammoniumcarbonate (34 mg, 0.35 mmol) and (2S)-benzyl 2-bromopentanoate (78 mg,0.30 mmol) were added. The reaction was refluxed for 24 hours. Thereaction was partitioned between 15 mL of 1 M aqueous Na₂CO₃ and 25 mLof CH₂Cl₂. The aqueous phase was extracted with 2×10 mL CH₂Cl₂, and thecombined organic phases were washed with 15 mL brine, dried (Na₂SO₄),then filtered and concentrated under reduced pressure to a brown oil(169 mg). The crude product was purified by silica gel chromatographyeluting with 3:1 CH₂Cl₂-hexane to produce 106 mg (68%) of the titlecompound as a waxy solid. ¹H NMR indicated the presence of twodiastereomeric products.

EXAMPLE 75Btrans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-((1R)-1-(N,N-dipropylaminocarbonyl)-1-butyl)pyrrolidine-3-carboxylicAcid Ethyl Ester

The resultant compound from Example 75A (101 mg, 0.180 mmol) and 30 mgof 10% palladium on charcoal were stirred in 2 mL EtOAc under 1atmosphere of H₂ for 4 hours. The reaction mixture was filtered througha plug of Celite, using 15 mL MeOH to wash the catalyst. The combinedfiltrate and wash were concentrated in vacuo to give 81.4 mg (96%) ofthe crude acid as a white solid.

The above crude acid was combined with HOBt hydrate (41 mg, 0.27 mmol),dipropylamine (26 mg, 0.26 mmol), and 4-methylmorpholine (37 mg, 0.37mmol) in 2 mL dry DMF. The solution was cooled to −15° C., then1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0.23mmol) was added. The mixture was stirred at -15° C. and allowed to warmslowly to room temperature overnight. The solvent was removed bydistillation under reduced pressure, and the residue was partitionedbetween 20 mL EtOAc and 10 mL of 1 M aqueous Na₂CO₃. The organic phasewas washed with 10 mL of brine, dried (Na₂SO₄), then filtered andconcentrated in vacuo. The crude product was purified by flashchromatography on silica gel, eluting with 1:2 Et2O-hexane. Furtherpurification of overlap fractions by preparative TLC eluting with 1:2Et₂O-hexane yielded 32 mg (34%) of a less polar product, and 44 mg (46%)of a more polar product.

EXAMPLE 75C(2R,3R,4R)-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-((1R)-1-(N,N-dipropylaminocarbonyl)-1-butyl)pyrrolidine-3-carboxylicAcid

The procedure of Example 73C was followed, with the substitution of theless polar isomer from Example 75B for the resultant product fromExample 73B, to provide the title compound in 94% yield. [α]D=−52° C.(c=0.235, CH₃OH). ¹H NMR (CD₃OD, 300 MHz) δ 0.55 (t, J=7 Hz, 3H), 0.87(t, J=7 Hz) and 0.87-0.94 (m, 6H total), 1.03-1.25 (br m, 2H), 1.25-1.68(br m, 4H), 1.90-2.07 (br m, 1H), 2.75-2.94 (br m, 2H), 2.94-3.02 (br m,2H), 3.20-3.40 (m, overlapping with CD₂HOD signal), 3.40-3.60 (br m,2H), 3.79 (s, 3H), 4.04 (br d, J=9 Hz, 1H), 5.92 (dd, J=3,5 Hz, 2H),6.72 (d, J=8 Hz, 1H), 6.79 (dd, J=1.5,8 Hz, 1H), 6.92-6.98 (br m, 3H),7.29-7.39 (m, 2H). MS m/z 525 (M+H)⁺.

EXAMPLE 76(2S,3S,4S)-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-((1R)-1-(N,N-dipropylaminocarbonyl)-1-butyl)pyrrolidine-3-carboxylic Acid

The procedure of Example 73C was followed, with the substitution of themore polar isomer from Example 75B for the resultant product fromExample 73B, to provide the title compound in 88% yield. [α]D=+58°(c=0.37, CH₃OH). ¹H NMR (CD₃OD, 300 MHz) δ 0.57 (br t, J=7 Hz, 3H),0.88-0.98 (m, 6H), 1.08-1.35. (br m, 2H), 1.35-1.68 (br m, 4H),1.75-1.90 (br m, 1H), 2.75-2.86 (br m, 2H), 3.10-3.30 (br m, 2H),3.51-3.65 (br m, 2H), 3.69 (s, 3H), 4.03-4.16 (br m, 2H), 5.91 (s, 2H),6.71-6.83 (m, 2H), 6.86-6.97 (m, 3H), 7.32 (br d, J=9 Hz, 2H). MS m/z525 (M+H)⁺.

EXAMPLE 77(2S,3S,4S)-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-((1S)-1-(N,N-dipropylaminocarbonyl)-1-butyl)pyrrolidine-3-carboxylicAcid EXAMPLE 77Atrans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-((1S)-1-(N,N-dipropylaminocarbonyl)-1-butyl)pyrrolidine-3-carboxylicAcid Ethyl Ester

(2R)-N,N-dipropyl 2-hydroxypentanamide (106 mg, 0.528 mmol, made bystandard procedure) was dissolved in 2 mL THF under an argon atmosphere,diisopropylethylamine (75 mg, 0.58 mmol) was added, then the solutionwas cooled to −20° C. Trifluoromethanesulfonic anhydride (95 μL, 159 mg,0.565 mmol) was added to the cooled solution over 1 minute, and thereaction mixture was stirred at −20° C. for 1 hour, and at roomtemperature for an additional 1 hour. The resulting slurry was recooledto 0° C., and a solution of the resultant compound from Example 6A (195mg, 0.528 mmol) and diisopropylethylamine (101 μL, 75 mg, 0.58 mmol) in3 mL of CH₂Cl₂ was added. The reaction was stirred at 0° C. for 3 hoursand for an additional 2 days at room temperature. TLC (Et₂O-hexane 1:2)indicated starting materials remained, so the mixture was warmed toreflux for 4 hours. The reaction was cooled, then partitioned between 30mL EtOAc and 15 mL of 1 M aqueous Na₂CO₃. The aqueous phase wasextracted with 15 mL EtOAc, then the combined organic phases were washedwith 20 mL brine, dried (Na₂SO₄), filtered and concentrated in vacuo toa yellowish oil. Purification by flash chromatography on silica geleluting with 1:2 Et₂O-hexane gave 19.9 mg (7%) of a less polar productand 20.1 mg (7%) of a more polar product. ¹H NMR spectra and MS were thesame as those of Example 76B.

EXAMPLE 77B(2S,3S,4S)-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-((1S)-1-(N,N-dipropylaminocarbonyl)-1-butyl)pyrrolidine-3-carboxylicAcid

The procedure of Example 73C was followed, with the substitution of theless polar isomer from Example 77A for the resultant product fromExample 73B, to provide the title compound in 100% yield. ¹H NMR (CD₃OD,300 MHz) and MS identical to those of Example 75C.

EXAMPLE 78(2R,3R,4R)-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-((1S)-1-(N,N-dipropylaminocarbonyl)-1-butyl)pyrrolidine-3-carboxylicAcid

The procedure of Example 73C was followed, with the substitution of themore polar isomer from Example 77A for the resultant product fromExample 73B, to provide the title compound in 88% yield. ¹H NMR (CD₃OD,300 MHz) and MS identical to those of Example 76.

EXAMPLE 79trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-3-(5-tetrazolyl)pyrrolidine

Carbonyldiimidazole (510 mg, 3.148 mmol) was added to 1.020 g (2.00mmol) of the compound resulting from Example 43 in 2.7 mL THF, and themixture was heated for 40 minutes at 50° C. The reaction mixture wascooled in an ice bath, and 25% solution of ammonia in methanol wasadded. After 30 minutes, the solid which had formed was filtered, washedwith ethanol and finally with ether to yield 850 mg (83%) of the3-carboxamide compound. m.p. 194-196° C.

Phosphorus oxychloride (1.06 g) was added to this amide in 7 mL ofpyridine, and the mixture was stirred 1 hour at room temperature.Dichloromethane was added, and the solution was washed with potassiumbicarbonate solution, dried over sodium sulfate, and concentrated. Theresidue was chromatographed on silica gel eluting with 2:1 hexane-ethylacetate to give .790 mg (96%) of the 3-carbonitrile compound.

To this nitrile in 5 mL toluene was added 385 mg of trimethyl tinchloride and 126 mg sodium azide. The mixture was heated 20 hours at125° C. (bath temp). After cooling, methanol (5 mL) was added, and thesolution was concentrated in vacuo. To the resulting residue was added 6mL of methanol and 6 mL of water containing 0.2 g phosphoric acid. Afterstirring 1 hour at room temperature, water was added and the mixtureextracted with dichloromethane. The combined organic extracts were driedand concentrated, and the resulting residue was crystallized from etherto give a solid. The solid was dissolved in sodium hydroxide solution,filtered from insoluble material and acidified with acetic acid to get532 mg (62%) of the title compound. m.p. 165-167° C. ¹H NMR (CDCl₃, 300MHz) δ 0.85 (t, J=7 Hz, 3H), 0.87 (t, J=7 Hz, 3H), 1.10-1.50 (m, 8H),3.0-3.6 (m, 8H), 3.70 (s, 3H), 3.7-38 (m, 1H), 3.90 (t, J=9 Hz, 1H),4.37 (d, J=9 Hz, 1H), 5.86 (s, 2H), 6.62 (d, J=8 Hz, 1H), 6.65-6.73 (m,3H), 6.95 (d, J=2 Hz, 1H), 7.11 (d, J=9 Hz, 2H).

EXAMPLE 80trans,trans-2-(4-Fluorophenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylicAcid

The title compound was prepared as an amorphous solid from methyl(4-flourobenzoyl) acetate and 5-(2-nitrovinyl)-1,3-benzodioxole usingthe procedures described in Examples 1 and 43. ¹H NMR (CDCl₃, 300 MHz) δ0.81 (t, J=7 Hz, 3H), 0.90 (t, J=7 Hz, 3H), 1.0-1.55 (m, 8H), 2.81 (d,J=13 Hz, 1H), 2.90-3.10 (m, 4H), 3.15-3.30 (m, 1H), 3.32-3.45 (m, 3H),3.55-3.65 (m, 1H), 3.86 (d, J=10 Hz, 1H), 5.94 (dd, J=2 Hz, 4 Hz, 2H),6.72 (d, J=8 Hz, 1H), 6.86 (d, J=8 Hz, 1H), 6.95-7.07 (m, 3H), 7.32-7.45(m, 2H).

EXAMPLE 81trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylicAcid

N,N-Dibutyl glycine (150 mg, 0.813 mmol), prepared by the method ofBowman, R. E., J. Chem. Soc. 1346 (1950), in 0.7 mL of THF was treatedwith 138 mg (0.852 mmol) carbonyldiimidazole and heated for 30 minutesat 50° C. After cooling to room temperature, 250 mg (0.678 mmol) ofethyltrans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate,the compound resulting from Example 6A, was added, and the mixture washeated at 45° C. for 30 minutes. The product was chromatographed onsilica gel, eluting with 1:1 hexane-ethyl acetate to give 306 mg of theintermediate ethyl ester.

The ester was hydrolyzed with sodium hydroxide in water and ethanol togive 265 mg of the title compound as a white powder. ¹H NMR (CDCl₃, 300MHz) δ rotational isomers—0.75 and 0.85 (2 t, J=7 Hz, 3H), 1.05-1.5 (m,8H), 2.65-3.20 (m, 6H) 3.43-3.70 (m, 3H), 3.72 (s, 3H), 3.87 (d, J=15Hz, 1H), 4.49 (dd, J=12 Hz, 6 Hz) and 5.23 (dd, J=12 Hz, 8 Hz) 2H, 5.90(dd, J=2 Hz, 4 Hz, 2H), 6.63-6.78 (m, 3H), 6.86 and 7.04 (d, J=9 Hz,2H), 7.22 (d, J=9 Hz, 2H).

EXAMPLE 82trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-n-butyl)-N-(n-propyl)aminocarbonylmethyl)pyrrolidine-3-carboxylicAcid

The title compound was prepared using the procedures described inExample 1. m.p. 160-162° C. ¹H NMR (CDCl₃, 300 MHz) rotational isomers δ0.69, 0.80, 0.84, 0.87 (four triplets, J=7 Hz, 6H), 1.00-1.52 (m, 6H),2.63 and 2.66 (two doublets, J=13 Hz, 1H), 2.90-3.10 (m, 4H), 3.23-3.61(m, 5H), 3.71 and 3.75 (two doublets, J=10 Hz, 1H), 3.78 (s, 3H),5.92-5.96 (m, 2H), 6.72 (d, J=8 Hz, 1H), 6.83-6.89 (m, 3H), 7.03 (d,J=2Hz, 1H), 7.81 (d, J=9 Hz, 2H).

EXAMPLE 83trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N,N-di(n-propyl)aminocarbonyl)ethyl]pyrrolidine-3-carboxylicAcid

The compound resulting from Example 6A (250 mg, 0.677 mmol), 205 mg(1.36 mmol) diallyl acrylamide (Polysciences, Inc.), and 10 mg aceticacid were heated at 85° C. in 0.75 mL of methoxyethanol for one hour.Toluene was added, and the solution was washed with bicarbonatesolution, dried, and concentrated. Chromatography on silica gel elutingwith 3:1 hexane-ethyl acetate gave 283 mg (80%) of the diallyl compound.

The diallyl compound was hydrogenated using 10% Pd/C catalyst (27 mg) inethyl acetate (25 mL) under a hydrogen atmosphere. The catalyst wasremoved by filtration, and the filtrate was concentrated to afford thedipropyl amide ethyl ester in 100% yield.

The ester was hydrolyzed to the title compound by the method of Example1D in 83% yield. ¹H NMR (CDCl₃, 300 MHz) δ 0.82 and 0.83 (two triplets,J=7 Hz, 6H), 1.39-1.54 (m, 4H), 2.35-2.60 (m, 3H), 2.80-3.07 (m, 5H),3.14-3.21 (m, 2H), 3.31-3.38 (m, 1H), 3.51-3.61 (m, 1H), 3.73 (d, J=12H,1H), 3.75 (s, 3H), 5.94 (s, 2H), 6,71 (d, J=9 Hz, 1H), 6.79-6.85 (m,3H), 7.04 (d, J=2 Hz, 1H)<7.32 (d, J=9 Hz, 2H).

EXAMPLE 84trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonyl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Example 8using dibutyl carbamoyl chloride, prepared by the method of Hoshino etal., Syn. Comm., 17: 1887-1892 (1987), as a starting material. ¹H NMR(CDCl₃, 300 MHz) δ 0.86 (t, J=7 Hz, 6H), 1.14-1.28 (m, 4H), 1.35-1.48(m, 4H), 2.81-2.94 (m, 2H), 3.11 (t, J=12 Hz, 1H), 3.30-3.41 (m, 2H),3.59-3.68 (m, 2H), 3.76 (s, 3H), 3.78-3.85 (m, 1H), 5.81 (d, J=9 Hz,1H), 5.94 (s, 2H), 6.73-6.86 (m, 5H), 7.24 (d, J=9 Hz, 2H).

EXAMPLE 85trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylicAcid Sodium Salt

Sodium hydroxide (48.2 mg of 98.3% pure, 1.184 mmol) in 2 mL of MeOH wasadded to the compound resulting from Example 43 (610 mg, 1.196 mmol.) in5 mL MeOH. The solution was concentrated to dryness, and the resultingpowder was stirred with heptane. The heptane was removed in vacuo togive a powder which was dried in the vacuum oven for 2 hours at 60° C.to yield 627.5 mg of the title compound.

EXAMPLE 86trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N,N-di(n-butyl)amino)ethyl]pyrrolidine-3-carboxylicAcid

A solution of the bromoethyl compound resulting from Example 61A (150mg), dibutylamine (150 mg) and sodium iodide (18 mg) in 0.75 mL ethanolwas heated at 80° C. for 1 hour. After cooling, toluene was added, andthe solution was washed with potassium bicarbonate solution, dried overNa₂SO₄ and concentrated. More toluene was added, and the solution wasagain concentrated to get rid of excess dibutylamine. The residue wasdissolved in warm heptane and filtered from a small amount of insolublematerial. The hepane was removed in vacuo to give 143 mg (87%) of theintermediate ethyl ester.

The ester was hydrolyzed by the method of Example 1D to give the titlecompound as a white powder. ¹H NMR (CD₃OD, 300 MHz) δ 0.89 (t, J=7 Hz,6H), 1.16-1.30 (m, 4H), 1.44-1.56 (m, 4H), 2.48-2.57 (m, 1H), 2.80-3.08(m, 8H), 3.14-3.25 (m, 1H), 3.31-3.38 (m, 1H), 3.59-3.60 (m, 1H), 3.74(s, 3H), 3.75 (d, J=10 Hz, 1H), 5.89 (s, 2H), 6.71 (d, J=9 Hz, 1H), 6.81(dd, J=9Hz, 2Hz, 1H), 6.90 (d, J=10 Hz, 2H), 6.96 (d, J=2Hz, 1H), 7.37(d, J=10 Hz, 2H).

EXAMPLE 87trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-{2-[N-(N,N-di(n-butyl)aminocarbonyl)-N-methylamino]ethyl}pyrrolidine-3-carboxylicAcid

Dibutyl carbamoyl chloride (135 mg) was added to the compound resultingfrom Example 61B (250 mg) and 150 mg triethylamine in 1 mLdichloromethane. After stirring 1 hour at room temperature, toluene wasadded, and the solution was washed with potassium bicarbonate -solution,dried over Na2SO4 and concentrated. The residue was chromatographed onsilica gel, eluting with a mixture of 38% EtOAc and 62% hexane to give194 mg of the ethyl ester intermediate.

The ester was hydrolyzed by the method of Example 1D to afford 141 mg ofthe title compound. ¹H NMR (CD₃OD, 300 MHz) δ 0.92 (t, J=7 Hz, 6H),1.21-1.32 (m, 4H), 1.42-1.53 (m, 4H), 2.62 (s, 3H), 2.65-2.76 (m, 1H),3.00-3.20 (m, 8H), 3.44-3.55 (m, 1H), 3.62-3.78 (m, 2H), 3.80 (s, 3H),4.07 (d, J=12 Hz, 1H), 5.93 (s, 2H), 6.75 (d, J=9 Hz, 1H), 6.87 (dd, J=9Hz, 2 Hz, 1H), 6.94 (d, J=10 Hz, 2H), 7.04 (d, J=2Hz, 1H), 7.40 (d J=10Hz, 2H).

EXAMPLE 88trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-(N-methanesulfonyl)carboxamide

Carbonyldiimidazole (75 mg, 0.463 mmol) was added to 150 mg (0.294 mmol)of the compound resulting from Example 43 in 0.4 mL of tetrahydrofuran,and the solution was stirred at 60° C. for 2 hours. After cooling, 50 mg(0.526 mmol) of methanesulfonamide and 68 mg (0.447 mmol) of DBU in 0.3mL of THF were added. The mixture was stirred at 45° C. for 2 hours. Thesolvents were removed in vacuo, and the residue was dissolved in water.A few drops of acetic acid were added, and the solution was lyophilizedto give 121 mg (70%) of the title compound. m.p. 170-173° C. ¹H NMR(CDCl₃, 300 MHz) δ 0.82 (t, J=7 Hz, 3H), 0.88 (t, J=7 Hz, 3H), 1.05-1.51(m, 8H), 2.75-2.86 (m, 2H), 2.83-3.25 (m, 4H), 3.17 (s, 3H), 3.32-3.50(m, 3H), 3.70-3.78 (m, 1H), 3.80 (s, 3H), 3.87 (d, J=10 Hz, 1H), 5.96(dd, J=2 Hz, 4 Hz, 2H), 6.74 (d, J=9 Hz, 1H), 6.84 (dd, J=9 Hz, 2 Hz,1H), 6.90 (d, J=10 Hz, 2H), 7.01 (d, J=2 Hz, 1H), 7.34 (d, J=10 Hz, 2H).

EXAMPLE 89trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-(N-benzenesulfonyl)carboxamide

The compound resulting from Example 43 was converted to the titlecompound by the method of Example 88 substituting benzenesulfonamide formethanesulfonamide. m.p. 169-171° C. for a sample recrystallized fromacetonitrile. ¹H NMR (CDCl₃, 300 MHz) δ 0.81(t, J=7 Hz, 3H), 0.89 (t,J=7 Hz, 3H), 1.02-1.50 (m, 8H), 2.65-2.80 (m, 2H), 2.90-3.25 (m, 4H),3.80-3.95 (m, 3H), 3.50-3.60 (m, 1H), 3.65 (d, J=10 Hz, 1H), 3.81 (s,3H), 5.94 (s, 2H), 6.70 (s, 2H), 6.81-6.90 (m, 3H), 7.17 (d, J=10 Hz,2H), 7.55 (t, J=7 Hz, 2H), 7.66 (t, J=7 Hz, 1H), 8.95 (d, J=7 Hz, 2H).

EXAMPLE 90trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[N,N-di(n-butyl)aminosulfonylmethyl]-pyrrolidine-3-carboxylicAcid

Chloromethyl sulfenyl chloride, prepared by the method of Brintzingeret. al., Chem. Ber. 85: 455-457 (1952), is reacted with dibutylamine bythe method of E. Vilsmaier described in Liebigs Ann. Chem. 1055-1063(1980) to give N,N-dibutyl chloromethyl sulfenyl chloride. Alternativelydimethyl(methylthio)sulfonium tetraflouroborate is reacted withdibutylamine to give N,N-dibutyl methylsulfenyl chloride which ischlorinated with N-chlorosuccinimide to give chloromethyl sulfenylchloride by the method of E. Vilsmaier, described in the abovereference.

The N,N-dibutyl chloromethyl sulfenyl chloride is reacted with thecompound resulting from Example 6A to give ethyltrans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[N,N-di(n-butyl)aminosulfenylmethyl]-pyrrolidine-3-carboxylate.This is oxidized with osmium tetroxide and N-methyl morpholine N-oxideby the method of S. Kaldor and M. Hammond, Tet. Lett. 32: 5043-5045(1991) to give the title compound after hydrolysis of the ethyl ester.

EXAMPLE 91trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[(N,N-di(n-butyl)aminocarbonyl-1-(RS)-ethyl]pyrrolidine-3-carboxylicAcid EXAMPLE 91A (±)-Dibutyl 2-bromopropanamide

2-Bromopropanoic acid (510 mg, 3.33 mmol) and 4-methylmorpholine (0.74mL, 6.73 mmol) were dissolved in 10 mL of CH₂Cl₂, the solution wascooled to 0° C. under a N₂ atmosphere, and then treated dropwise withisobutyl chloroformate (0.45 mL, 3.5 mmol). After 10 minutes at 0° C.,dibutylamine (0.57 mL, 3.4 mmol) was added. The reaction was stirred at0° C. for 1 hour and for an additional 16 hours at room temperature. Themixture was partitioned with 25 mL of 1.0 M aqueous Na₂CO₃ solution,then the organic phase was washed sequentially with 25 mL of 1 M aqueousNaHSO₄ and 25 mL brine, dried (Na₂SO₄), filtered, and concentrated underreduced pressure to afford 698 mg (2.64 mmol, 79%) of the crudebromoamide as a colorless oil. ¹H NMR (CDCl₃, 300 MHz) δ 0.93 (t, J=7Hz) and 0.97 (t, J=7.5 Hz, 6H total), 1.26-1.60 (m, 7H), 1.60-1.78 (m, 1H), 1.82 (d, J=6 Hz, 3H), 3.04-3.27 (m, 2H), 3.42-3.64 (m, 2H), 4.54 (q,J=7H, 1H). MS (DCl/NH₃) m/e 264 and 266 (M+H)⁺.

EXAMPLE 91B trans,trans andcis,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-((N,N-di(n-butyl)amino)carbonyl-1-(RS)-ethyl)pyrrolidine-3-carboxylicAcid Ethyl Ester

A solution of the resultant mixture of trans,trans and cis,transcompounds from Example 1C (232 mg, 0.628 mmol) and the resultantcompound from Example 91A (183 mg, 0.693 mmol) in 2 mL of CH₃CN wastreated with diisopropylethylamine (0.22 mL, 1.3 mmol). The solution wasstirred at 60-80° C. under a N₂ atmosphere for 16 hours. The reactionwas concentrated under reduced pressure, then the residue waspartitioned between 30 mL Et₂O and 10 mL of 1 M aqueous Na2CO₃ solution.The organic phase was washed with 20 mL water and 20 mL brine, driedover Na₂SO₄, filtered and concentrated under reduced pressure to affordthe crude amino amide as a brown oil (339 mg, 98% crude). The productwas obtained by flash chromatography on silica gel eluting with 20%EtOAc-hexane to provide 224 mg (70%) of the title compounds as a mixtureof 4 diastereomers. ¹H NMR (CDCl₃, 300 MHz) δ 0.66-1.55 (several m,19H), 2.63-3.00 (m, 3H), 3.05-3.39 (m, 2H), 3.40-3.76 (m, 4H), 3.78-3.80(4 s, 3H), 3.84-4.25 (m, 2.6H), 4.38 (d, J=10.5 Hz, 0.2H) and 4.58 (d,J=10.5 Hz, 0.2H), 5.90-5.97 (m, 2H), 6.68-6.96 (m, 5H), 7.38-7.43 (m,2H). MS (DCl/NH₃) m/e 553 (M+H)⁺.

EXAMPLE 91Ctrans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-((N,N-dibutylamino)carbonyl-1-(RS)-ethyl)pyrrolidine-3-carboxylicAcid

The procedure of Example 73C was used, substituting the resultantcompound from Example 91 B for the resultant compound from Example 73Bto give the title compound in 61% yield. ¹H NMR (CD₃OD, 300 MHz) δ0.70-1.05 (several m, 8H), 1.14 (d, J=6 Hz, 2H), 1.17-1.55 (m, 6H),2.79-3.039m, 3.5H), 3.20-3.65 (br m, 4.6H plus CD₂HOD), 3.70-3.78 (m,0.4H), 3.79 (s, 3H), 3.98 (d, J=8 Hz, 0.6H), 4.06 (t, J=7.5 Hz, 0.4H),4.25 (d, J=8 Hz, 0.4H), 5.92 (s) and 5.94 (s, 2H total 6H), 6.73 (d,J=2.5 Hz) and 6.75 (d, J=3 Hz, 1H total), 6.78-6.85 (m, 1 H), 6.91-7.00(m, 3H), 7.30-7.38 (m, 2H). MS (DCl/NH₃) m/e 525 (M+H)⁺. Anal calcd forC₃₀H₄₀N₂O₆.0.5H₂O: C, 67.52; H, 7.74; N, 5.25. Found: C, 67.63; H, 7.65;N, 5.21.

EXAMPLE 92trans,trans-2-(Pentyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylicAcid EXAMPLE 92A Methyl2-(4-hexenoyl)-4-nitro-3-(1,3-benzodioxole-5-yl)butyrate

A solution of methyl 3-oxo-6-octenoate (502 mg, 2.95 mmol) in 10 mL ofisopropanol was added to a solution of 5-(2-nitrovinyl)-1,3-benzodioxole(712 mg, 3.69 mmol) in 10 mL THF, then DBU (22 μL, 0.15 mmol) was added.The resulting reddish solution was stirred at room temperature for 20minutes. TLC (ethyl acetate-hexane, 1:3) indicated complete consumptionof ketoester. The solution was concentrated in vacuo and flashchromatographed on silica gel eluting with 18% ethyl acetate in hexaneto produce 879 mg (2.42 mmol, 82%) of the title compound as a mixture ofdiastereomers in a 1:1 ratio. ¹H NMR (CDCl₃, 300 MHz) δ 1.55-1.66 (m,3H), 2.02-2.17 (br m, 1H), 2.20-2.37 (m, 1.5H), 2.49-2.76 (m, 1.5H),3.57 (s, 1.5H), 3.74 (s, 1.5H), 3.97 (d, J=7.5H, 0.5 H) and 4.05 (d, J=8Hz, 0.5H), 4.10-4.20 (m, 1H), 4.68-4.82 (m, 2H), 5.06-5.52 (m, 2H), 5.95(2s, 2H), 6.65 (m, 1H), 6.68 (br s, 1H), 6.75 (d, 7.5 Hz, 1H). MS(DCl/NH₃) m/e 381 (M+NH₄)⁺. Anal calcd for C₁₈H₂₁NO₇: C, 59.50; H, 5.82;N, 3.85. Found: C, 59.32; H, 5.71; N, 3.72.

EXAMPLE 92B Methyltrans,trans-2-(Pentyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylate

The procedures of Example 1B and Example 1C were followed, with thesubstitution of the resultant compound from Example 92A for theresultant compound from Example 1A, and the substitution of the thisresultant compound for the resultant compound from Example 1B, toprovide the title compound in crude form as a yellow oil. This crudecompound was epimerized under the following conditions. A solution ofthe crude compound (660 mg, 2.07 mmol) in 3 mL methanol was treated witha solution of sodium methoxide (made by the addition of sodium metal (14mg, 0.61 mmol) to 1 mL of methanol). The resultant solution was heatedat reflux for 18 hours. The reaction was concentrated under reducedpressure, and the residue was partitioned between 25 mL saturated NaHCO₃diluted with 10 mL water and 30 mL of CH₂Cl2. The aqueous phase wasextracted (2×30 mL CH₂Cl₂), then the combined organic phases were washedwith 20 mL brine, dried over Na₂SO4, filtered and the filtrateconcentrated under reduced pressure to afford the crude product.Purification by flash chromatography on silica gel eluting with 3.5%methanol in CH₂Cl₂ gave 336 mg (57%) the title compound as a yellow oil.¹H NMR (CDCl₃, 300 MHz) δ 0.90 (br t, 3H), 1.25-1.70 (br m, 8H),1.83-2.02 (br s, 2H), 2.58 (dd, J=8,9 Hz, 1H), 2.99 (dd, J=8,14 Hz, 1H),3.34-3.45 (m, 2H), 3.53 (q, J=9 Hz, 1H), 3.66 (s, 3H), 5.94 (s, 2H),6.65-6.75 (m, 3H). MS (DCl/NH₃) m/e 320 (M+H)⁺. Anal calcd forC₁₈H₂₅NO₄: C, 67.69; H, 7.89; N, 4.39. Found: C, 67.39; H, 7.84; N,4.37.

EXAMPLE 92Ctrans,trans-2-(Pentyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylicAcid

The procedures of Example 1B-1D were used, with the substitution of theresultant compound from Example 92A for the resultant compound fromExample 1B, to provide the title compound as a white foam. ¹H NMR(CDCl₃, 300 MHz) δ 0.87 (br t) and 0.89 (br t, 6H total), 0.97 (t, J=7.5Hz, 3H), 1.21-1.42 (br m, 10), 1.43-1.78 (br m, 6H), 2.76 (t, J=7 Hz, 1H), 3.02-3.30 (br m, 6H), 3.40-3.60 (m, 3H), 3.73 (d, J=14Hz, 1 H), 5.98(AB, 2H), 6.70 (d, J=7Hz, 1H), 6.77 (dd, J=1.5,7 Hz, 1H), 6.89 (d, J=1.5Hz, 1H). MS (DCl/NH₃) m/e 475 (M+H)⁺. Anal calcd for C₂₇H₄₂N₂O₅.0.5H₂O:C, 67.05; H, 8.96; N, 5.79. Found: C, 67.30; H, 8.77; N, 5.68.

EXAMPLE 93trans,trans-2-(Pentyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-propylsulfonylamino)ethyl]pyrrolidine-3-carboxylicAcid EXAMPLE 93A Methyltrans,trans-2-(Pentyl)-4-(1,3-benzodioxol-5-yl)-1-(2-bromoethyl)pyrrolidine-3-carboxylate

The procedure of Example 61 A was used, with the substitution of theresultant compound from Example 92B for the resultant compound fromExample 1C, to provide the title compound as a yellow oil. ¹H NMR(CDCl₃, 300 MHz) δ 0.89 (br t, J=7 Hz, 3H), 1.24-1.40 (br m, 6H),1.60-1.80 (br m, 2H), 2.61-2.75 (m, 2H), 2.76-2.91 (m, 2H), 3.10-3.22(m, 2H), 3.36-3.47 (m, 2H), 3.68 (s, 3H), 5.92 (s, 2H), 6.69-6.77 (m,2H), 6.90-6.94 (m, 1H). MS (DCl/NH₃) m/e 426, 428 (M+H)⁺.

EXAMPLE 93B Methyltrans,trans-2-(Pentyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-propylsulfonylamino)ethyl]pyrrolidine-3-carboxylate

A solution of the resultant compound from Example 93A (102 mg, 0.24mmol) and tetrabutylammonium iodide (6 mg, 16 μmol) in 1 mL EtOH wastreated with propylamine (60 μL, 0.73 mmol). The solution was warmed to80° C. for 4 hours. The reaction was concentrated under reducedpressure, then the residue was dissolved in 35 mL ethyl acetate andextracted with 2×15 mL of 1 M aqueous Na₂CO₃. The organic phase waswashed with 15 mL brine, then dried over Na₂SO₄, filtered andconcentrated under reduced pressure to provide the crude secondary amineas a yellow oil (94.2 mg). The crude amine was dissolved in 1 mL ofCH₂Cl₂, diiosopropylethylamine (65 μL, 0.373 mmol) was added, followedby propylsulfonyl chloride (29 μL, 0.26 mmol). The solution was stirredat room temperature for 4 hours. The reaction was quenched with 10%aqueous citric acid (to pH 4), and the mixture was extracted with 2×3 mLCH₂Cl₂. The combined organic extracts were washed with 2 mL brine, thendried over Na2SO4, filtered, concentrated in vacuo. Purification byflash chromatography eluting with 20% ethyl acetate in hexane provided65.0 mg (53%) of the title compound as a waxy solid. R_(f)=0.17(20%EtOAc-hexane). MS (DCl/NH₃) m/e 511 (M+H)⁺.

EXAMPLE 93Ctrans,trans-2-(Pentyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-propylsulfonylamino)ethyl]pyrrolidine-3-carboxylicAcid

The procedure of Example 71C was followed, with the substitution of theresultant compound from Example 93B for the resultant compound fromExample 71B, to provide the title compound as a white foam (47 mg, 80%),R_(f)=0.14 (5% MeOH-CH₂Cl₂). ¹H NMR (CDCl₃, 300 MHz) δ 0.88 (br t) and0.92 (t, J=7 Hz, 6H total), 1.22-1.52 (br m, 6H), 1.63 (sextet, J=8 Hz,2H), 1.75-2.10 (br m, 4H), 2.89-2.98 (m, 2H), 3.05 (br t, J=9 Hz, 1 H),3.10-3.30 (m, 3H), 3.30-3.80 (br m, 7H), 5.94 (s, 2H), 6.71 (t, J=8 Hz,1H), 6.77 (dd, J=1.5,8 Hz, 1H), 6.89 (d, J=1.5 Hz, 1H). MS (DCl/NH₃) m/e497 (M+H)⁺.

EXAMPLE 94trans,trans-2-(Propyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylicAcid EXAMPLE 94A Ethyl2-(4-butanoyl)-4-nitro-3-(1,3-benzodioxole-5-yl)butyrate

The procedure of Example 92A was followed, with the substitution ofethyl butyryl acetate for methyl 3-oxo-6-octenoate, to provide the titlecompound as a mixture of trans and cis isomers (47 mg, 80%), R_(f)=0.28(25% EtOAc-hexane). ¹ H NMR (CDCl₃, 300 MHz) δ 0.74 (t, J=7.5 Hz) and0.91 (t, J=7.5 Hz, 3H total), 1.08 (t, J=7 Hz) and 1.28 (t, J=7 Hz, 3Htotal), 1.45 (sextet, J=7 Hz, 1.5H), 1.63 (sextet, J=7 Hz, approx.1.5H), 2.17 (t, J=7 Hz) and 2.24 (t, J=7 Hz, 0.5H total)2.40-2.54 (m,1H), 2.60 (t, J=7.5 Hz) and 2.67 (t, J=7.5 Hz, 0.5H total), 3.93-4.09(m, 2H), 4.10-4.20 (br m, 1H), 4.23 (q, J=7 Hz, 1H), 4.67-4.85 9m, 2H),5.94 (s, 2H), 6.62-6.75 (m, 3H). MS (DCl/NH₃) m/e 369 (M+NH₄)⁺. Analcalcd for C₁₇H₂₁NO₇: C, 58.11; H, 6.02; N, 3.99. Found: C, 58.21; H,5.98; N, 3.81.

EXAMPLE 94B Ethyltrans,trans-2-(Propyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylate

The procedure of Example 92B was followed, with the substitution of theresultant compound from Example 94A for the resultant compound fromExample 92A, to afford the title compound. MS (DCl/NH₃) m/e 306 (M+H)⁺.

EXAMPLE 94Ctrans,trans-2-(Propyl)-4-(1,3-benzodioxol-5-yl)-1-((N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

The procedure of Example 92C was followed, with the substitution of theresultant product from Example 94B for the resultant product fromExample 92B, to give the title compound. ¹H NMR (CDCl₃, 300 MHz) δ 0.89(t, J=7.5 Hz), 0.92 (t, J=7.5 Hz), and 0.97 (t, J=7.5H, 9H total),1.22-1.80 (br m, 12H), 2.83 (t, J=7.5 Hz, 1H), 3.40-3.55 (br m, 2H),3.55-3.68 (m, 1H), 3.78 (d, J=15 Hz, 1H), 5.92 (q, J=1 Hz, 2H), 6.70 (d,J=8 Hz, 1H), 6.79 (dd, J=1 Hz,8Hz, 1H), 6.90 (d, J=l Hz, H). MS(DCl/NH₃) m/e 447 (M+H)⁺. Anal calcd for C₂₅H₃₈N₂O₅.0.5 H₂O: C, 65.91;H, 8.63; N, 6.15. Found: C, 65.91; H, 8.68; N, 5.94.

EXAMPLE 95(2R,3R,4S)-(+)-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(tert-butyloxycarbonyl-aminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid EXAMPLE 95Atrans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(tert-butyloxycarbonylaminocarbonylmethyl]pyrrolidine-3-carboxylicAcid

The resulting mixture of 64% trans,trans- and cis,trans-pyrrolidinesresulting from Example 1C (3.01 g, 8.15 mmol) was dissolved in 50 mL ofmethylene chloride. To this was added dropwise a solution ofdi-tert-butyl dicarbonate (1.96 g, 8.97 mmol) in 20 mL methylenechloride under a nitrogen atmosphere, and the resulting solution wasstirred 30 minutes at which point TLC (ethyl acetate:hexane, 1:1)indicated that all of the starting material was consumed. The reactionmixture was concentrated and dried under high vacuum to give 3.94 g ofthe ethyl ester as a yellow-brown oil. ¹H NMR (CDCL₃, 300 MHz) δ 0.99,1.07 (br t, br t, J=7 Hz, 3H), 1.11-1.62 (several br m, 9H), 3.05 (br m,1H), 3.44-3.95 (m, 3H), 3.81 (s, 3H), 4.04 (q, J=7 Hz, 1H), 4.14-4.28(br m, 1H), 4.89-5.24 (br m, 1H), 5.94 (d, J=3 Hz, 2H), 6.69-6.90 (m,5H), 7.06-7.20 (m, 2H). MS (DCl/NH₃) m/e 470 (M+H)⁺.

To the ethyl ester dissolved in 170 mL of ethanol was added a solutionof lithium hydroxide (1.06 g, 25.17 mmol) in 60 mL of water. Thereaction mixture was vigorously stirred for 18 hours under a nitrogenatmosphere. The reaction mixture was concentrated to remove ethanol,diluted with 250 mL of water and extracted three times with 250 mL ofether. The organic phase acidified to slight cloudiness (pH ˜7) with 1 Nhydrochloric acid, then to pH 4 with 10% citric acid and extracted with5% ethanol in methylene chloride (3×100 mL). The combined organic layersdried (Na₂SO₄), filtered, concentrated and dried on high vacuum to givethe title compound as a white foam (2.19 g, 60%). ¹H NMR (CDCl₃, 300MHz) δ 1.16 (v br s, 9H), 3.11 (br m, 1H), 3.50-3.64 (m, 2H), 3.81 (s,3H), 4.24 (br m, 1H), 4.96 (br m, 1H), 5.94 (s, 2H), 6.71-6.79 (m, 3H),6.84-6.91 (m, 2H), 7.19 (d, J=9 Hz, 2H). MS (DCl/NH₃) m/e 442 (M+H)⁺.

EXAMPLE 95B(2R,3R,4S)-(+)-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(tert-butyloxycarbonylaminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

The compound resulting from Example 95A (2.15 g, 4.86 mmol) and(+)-cinchonine (1.43 g₉,4.86 mmol) were added to 100 mL of methylenechloride; this suspension was swirled with warming as necessary to getall solids to dissolve. The solution was then concentrated and dried onhigh vacuum to a white foam. This material was crystallized from amixture of refluxing chloroform (64 mL) and hexane (360 mL). Theresulting crystals were isolated by filtration and recrystallized underthe same conditions seven additional times. Each time the resultingcrystals and filtrate were monitored by ¹H NMR and chiral HPLC. Theamount of (2S,3S,4R)-(−)-enantiomer decreased first in the crystals andthen in the filtrate with the predetermined endpoint achieved when the(2S,3S,4R)-(−)-enantiomer could no longer be detected in the filtrate.The pure (2R,3R,4S)-(+)- enantiomer thus obtained was partitionedbetween 100 mL of 10% citric acid and 100 mL of ether. The aqueous layerwas further extracted twice with 100 mL of ether. The combined etherlayers were washed with brine, dried (Na₂SO₄), filtered, concentratedand dried on high vacuum to a white powder (550 mg, 55% of theoretical50% maximum, >99.5 ee). ¹H NMR (CDCl₃, 300 MHz) δ 1.05-1.50 (br m, 9H),3.12 (br m, 1H), 3.50-3.65 (m, 2H), 3.81 (s, 3H), 4.24 (m, 1H), 4.96 (brm, 1H), 5.95 (s, 2H), 6.70-6.79 (m, 3H), 6.86 (d, J=9 Hz, 2H), 7.19 (d,J=9 Hz, 2H). MS (DCl/NH₃) m/e 442 (M+H)⁺.

EXAMPLE 95C (2R,3R,4S)-(+)-Ethyl2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate

The compound resulting from Example 95B (251 mg, 0.568 mmol) wasdissolved in 20 mL of a saturated solution of anhydrous HCl(g) inanhydrous ethanol. The resulting solution was heated at 50° C. withstirring for 18 hours at which point all of the precipitated solid haddissolved. The reaction mixture was concentrated to a solid which waspartitioned between 0.8 M aqueous sodium carbonate (50 mL) and methylenechloride (50 mL). The aqueous layer was further extracted with methylenechloride (2×50 mL). The combined organic layers were dried (Na₂SO₄),filtered, concentrated and dried under high vacuum to give the titlecompound as an almost colorless oil (158 mg, 69%). ¹H NMR (CDCl₃, 300MHz) δ 1.11 (t, J=7 Hz, 3H), 2.18 (v br s, 1H), 2.93 (t, J=9 Hz, 1H),3.19,3.22 (dd, J=7 Hz, 1H), 3.50-3.69 (m, 2H), 3.80 (s, 3H), 4.07 (q,J=7 Hz, 2H), 4.49 (d, J=9 Hz, 1H), 5.94 (s, 2H), 6.73 (d, J=2 Hz, 2H),6.81-6.92 (m, 3H), 7.34-7.41 (m, 2H). MS (DCl/NH₃) m/e 370 (M+H)⁺.

EXAMPLE 95D(2R,3R,4S)-(+)-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(tert-butyloxycarbonyl-aminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

To the resulting compound from Example 95C (131 mg, 0.355 mmol) wasadded, diisopropylethylamine (137 mg, 185 μL, 1.06 mmol), acetonitrile(2 mL), N,N-di-(n-butyl)bromoacetamide (133 mg, 0.531 mmol), and themixture was heated at 50° C. for 1.5 hours. The reaction mixture wasconcentrated to a solid, dried under high vacuum, and purified bychromatography on silica gel eluting with 1:3 ethyl acetate-hexane togive pure ester as a colorless oil. ¹H NMR (CDCl₃, 300 MHz) δ 0.81 (t,J=7 Hz, 3H), 0.88 (t, J=7 Hz, 3H), 1.10 (t, J=7 Hz, 3H), 1.00-1.52 (m,8H), 2.78 (d, J=14 Hz, 1H), 2.89-3.10 (m, 4H), 3.23-3.61 (m, 5H), 3.71(d, J=9 Hz, 1H), 3.80 (s, 3H), 4.04 (q, J=7 Hz, 2H), 5.94 (dd, J=1.5 Hz,2H), 6.74 (d, J=9 Hz, 1H), 6.83-6.90 (m, 3H), 7.03 (d, J=2 Hz, 1H), 7.30(d, J=9 Hz, 2H). MS (DCl/NH₃) m/e 539 (M+H)⁺.

To the ethyl ester dissolved in 7 mL of ethanol was added a solution oflithium hydroxide (45 mg, 1.06 mmol) in water (2.5 mL). The mixture wasstirred for 1 hour at ambient temperature and then warmed slowly to 40°C. over 2.5 hours at which point all of the starting material had beenconsumed. The reaction mixture was concentrated to remove the ethanol,diluted with 60 mL water and extracted with ether (3×40 mL). The aqueoussolution was treated with 1 N aqueous hydrochloric acid until cloudy,and the pH was then adjusted to ˜4-5 with 10% aqueous citric acid. Thismixture was extracted with 1:19 ethanol-methylene chloride (3×50 mL).The combined extracts were dried (Na₂SO₄), filtered, concentrated anddried under high vacuum to give the title compound as a white foam (150mg, 83%). ¹H NMR (CDCl₃, 300 MHz) δ 0.80 (t, J=7 Hz, 3H), 0.88 (t, J=7Hz, 3H), 1.08 (m, 2H), 1.28 (m, 3H), 1.44 (m, 3H), 2.70-3.77 (svr br m,12H), 3.79 (s, 3H), 5.95 (m, 2H), 6.75 (d, J=8 Hz, 1H), 6.87 (br d, J=8Hz, 3H), 7.05 (br s, 1H), 7.33 (v br s, 2H). MS (DCl/NH₃) m/e 511(M+H)⁺. [α]²²=+74.42°. Anal calcd for C₂₉H₃₈N₂O₆.0.5 H₂O: C ,67.03; H,7.56; N, 5.39. Found: C, 67.03; H, 7.59; N, 5.33.

EXAMPLE 95E Alternate Preparation of(2R,3R,4S)-(+)-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(tert-butyloxycarbonylaminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

The product of Example 95A (2.858 g) was suspended in 10 mL of EtOAc.0.7833 g of R (+) alpha methyl benzylamine in 3 mL ethyl acetate wasadded. On swirling all of the solids were dissolved. The ethyl acetatewas removed in vacuum. Ether (13 ml) was added to the residue. When allof the residue had dissolved, 5 mg of seed crystals were added and thesecrystals were crushed with a metal spatula while cooling in ice. Theproduct crystallized very slowly. After 1 hour the solid was filteredand washed with ether giving 1.4213 g, m.p. 163-167°. The filtrate wasconcentrated, cooled and scratched with a spatula to give a second crop0.1313 g, m.p. 164-168°. The filtrate was concentrated again and put inthe refrigerator and let stand overnight giving 1.6906 g, m.p. 102-110°.(HPLC of this showed 20% of the desired enantiomer and 80% of theunwanted enantiomer.)

The first two batches of crystallized material were combined andsuspended in 20 mL dichloromethane (Note: the unwanted isomer is moresoluble in dichloromethane) and stirred for 2 minutes. The mixture wasconcentrated, but not to dryness, and ether (10 mL) was added. Afterstirring for a few minutes the crystals were filtered. Yield: 1.401 g,m.p. 164-172°.

Treatment of the crystalline product with 10% citric acid and etheraccording the method described in Example 95B provided the titlecompound.

EXAMPLE 96trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-butyrylamino)ethyl]pyrrolidine-3-carboxylicAcid

The title compound was prepared by the methods described in Example 61,but substituting propylamine for methylamine in Example 61B and butyrylchloride for isobutyryl chloride in Example 61C. The product waspurified by preparative HPLC (Vydac μC18) eluting with a 10-70% gradientof CH₃CN in 0.1% TFA. The desired fractions were lyophilized to give theproduct as a white solid. ¹H NMR (CDCl₃, 300 MHz) δ 0.80 (m, 3H), 0.90(t, 3H, J=8 Hz), 1.42 (m, 2H), 1.58 (heptet, 2H, J=8 Hz), 2.20 (t, 3H,J=8 Hz), 2.94 (br m, 2H), 3.10 (br m, 2H), 3.48 (br m, 4H), 3.76 (br m,2H), 3.78 (s, 3H), 4.30 (br s, 1H), 5.95 (s, 2H), 6.75 (d, 1H, J=8 Hz),6.84 (m, 1H), 6.85 (d, 2H, J=8 Hz), 7.04 (d, 1H, J=1 Hz), 7.40 (d, 2H,J=8 Hz). MS (DCl/NH₃) m/e 497 (M+H)⁺. Anal calcd for C₂₈H₃₆N₂O₆.1.0 TFA:C, 58.82; H, 6.42; N, 4.57. Found: C, 58.77; H, 6.30; N, 4.42.

EXAMPLE 97trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-Propyl-N-(ethylaminocarbonyl)amino)ethyl]pyrrolidine-3-carboxylicAcid

The title compound was prepared by the methods described in Example 61,but substituting propylamine for methylamine in Example 61B and ethylisocyanate for isobutyryl chloride in Example 61C. The crude product waspurified by trituration with 1:1 diethyl ether-hexane. The resultingsolid was dissolved in CH₃CN and water and lyophilized to give theproduct as a white solid. ¹H NMR (CDCl₃, 300 MHz) mixture of rotamers δ0.80 (t, J=8 Hz) and 1.05 (t, J=8 Hz) and 1.20 (m) and 1.42 (m) total of8H for the four peaks, 2.35 (br s, 1H), 2.70 (m, 1H), 3.0 (m, 3H), 3.2(m, 3H), 3.25 (dq, 1H, J=1,8 Hz), 3.42 (m, 1H), 3.6 (m, 1H), 3.75 (m,1H), 3.78 (s, 3H), 4.8 (br s, 1H), 5.95 (s, 2H), 6.74 (d, 1H, J=8 Hz),6.85 (m, 3H), 7.00 (s, 1H), 7.30 (d, 2H, J=8 Hz). MS (DCl/NH₃) m/e 498(M+H)⁺. Anal calcd for C₂₇H₃₅N₃O₆.0.75 H₂O: C, 63.45; H, 7.20; N, 8.22.Found: C, 63.38; H, 7.29; N, 8.44.

EXAMPLE 98trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-butyl-N-butyrylamino)ethyl]pyrrolidine-3-carboxylicAcid

The title compound was prepared by the methods described in Example 61,but substituting butylamine for methylamine in Example 61B and butyrylchloride for isobutyryl chloride in Example 61C. The crude product waspurified by trituration with 1:1 diethyl ether-hexane. The resultingsolid was dissolved in CH₃CN and water and lyophilized to give theproduct as a white solid. ¹H NMR (CDCl₃, 300 MHz) δ 0.80 (m, 3H), 0.90(t, 3H, J=8 Hz), 1.45 (m, 4H), 1.6 (m, 2H), 2.20 (t, 3H, J=8 Hz), 2.94(br m, 2H), 3.10 (br m, 2H), 3.5 (br m, 4H), 3.80 (br m, 2H), 3.82 (s,3H), 4.30 (br s, 1H), 5.95 (s, 2H), 6.75 (d, 1H, J=8 Hz), 6.84 (m, 1H),6.85 (d, 2H, J=8 Hz), 7.04 (d, 1H, J=1 Hz), 7.40 (d, 2H, J=8 Hz). MS(DCl/NH₃) m/e 511 (M+H)⁺. HRMS calcd for C₂₉H₃₈N₂O₆: 511.2808. Found:511.2809.

EXAMPLE 99trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-ethoxycarbonylamino)ethyl]pyrrolidine-3-carboxylicAcid

The title compound was prepared by the methods described in Example 61,but substituting propylamine for methylamine in Example 61B and ethylchloroformate for isobutyryl chloride in Example 61C. The crude productwas purified by trituration with 1:1 diethyl ether-hexane. The resultingsolid was dissolved in CH₃CN and water and lyophilized to give theproduct as a white solid. ¹H NMR (CDCl₃, 300 MHz) δ 0.80 (t, 3H, J=8Hz), 1.05 (m, 2H), 1.22 (m, 3H), 1.45 (m, 3H), 2.08 (br s, 1H), 2.75 (m,1H), 2.88 (br q, 2H, J=8 Hz), 3.08 (br m, 2H), 3.27 (br m, 2H), 3.44 (m,1H), 3.54 (dt, 1H, J=1,8 Hz), 3.63 (d, 1H, J=8 Hz), 3.78 (s, 3H), 4.02(br d, 2H), 5.93 (s, 2H), 6.72 (d, 1H, J=8 Hz), 6.81 (dd, 1H, J=1,8 Hz),6.85 (d, 2H, J=8 Hz), 7.00 (s, 1H), 7.30 (d, 2H, J=8 Hz). MS (DCl/NH₃)m/e 499 (M+H)⁺. Anal calcd for C₂₇H₃₄N₂O₇.0.5 H₂O: C, 63.89; H, 6.95; N,5.52. Found: C, 64.03; H, 6.71; N, 5.30.

EXAMPLE 100trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-methyl-N-(2-ethylbutyryl)amino)ethyl]pyrrolidine-3-carboxylicAcid

To the compound resulting from Example 61B (190 mg) dissolved in THF (2mL) was added HOBt (60 mg), EDCl (85 mg), N-methylmorpholine (50 μL),and DMF (2 mL). 2-Ethylbutyric acid was added and the solution stirredovernight at ambient temperature. Water (10 mL) was added, and themixture was extracted with EtOAc (2×25 mL). The combined organicextracts were washed with saturated sodium bicarbonate solution, 1 NH₃PO₄, and brine, dried with Na₂SO₄, and evaporated to give an oil whichwas purified by. flash chromatography on silica gel eluting with 1:3EtOAc-hexane. The resulting ethyl ester was saponified by the proceduredescribed in Example 61C. The crude product was dissolved in CH₃CN andwater and lyophilized to give the product as a white solid. ¹H NMR(CDCl₃, 300 MHz) (mixture of rotamers) δ 0.66, 0.74, 0.80, 0.88 (alltriplets, total of 6H, J=8 Hz), 1.05 (m, 2H), 1.25-1.75 (m, 5H), 2.16(m, 1H), 2.32 (m, 1H), 2.45 (m, 1H), 2.70 (m, 1H), 2.86, 2.94 (s, total3H), 2.95 (m, 1H), 3.35 (m, 1H), 3.52 (m, 2H), 3.65 (m, 1H), 3.80 (s,3H), 5.94, 5.96 (s, total 2H), 6.73 (m, 1H), 6.84 (m, 3H), 6.97 (m, 1H),7.30 (m, 2H). MS (DCl/NH₃) m/e 497 (M+H)⁺. Anal calcd forC₂₈H₃₆N₂O₆.0.25 H₂O: C, 67.1 1; H, 7.34; N, 5.59. Found: C, 67.13; H,7.24; N, 5.56.

EXAMPLE 101trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-methyl-N-(2-propylvaleryl)amino)ethyl]pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedure described in Example100, but substituting 2-propylpentanoic acid for 2-ethylbutyric acid.The crude product was purified by preparative HPLC (Vydac μC18) elutingwith a 10-70% gradient of CH₃CN in 0.1% TFA. The desired fractions werelyophilized to give the product as a white solid. ¹H NMR (CDCl₃, 300MHz) δ 0.79 (t, 3H, J=8 Hz), 0.82 (t, 3H, J=8 Hz), 1.10 (m, 4H), 1.2-1.5(m, 4H), 2.55 (m, 1H), 2.96 (s, 3H), 3.15 (br m, 1H), 3.32 (br m, 1H),3.56 (m, 2H), 3.68 (m, 1H) 3.68 (s, 3H), 3.70 (m, 1H), 3.80 (m, 2H),4.65 (br d, 1H), 5.92 (s, 2H), 6.75 (d, 1H, J=8 Hz), 6.84 (m, 1H), 6.85(d, 2H, J=8 Hz), 7.05 (s, 1H), 7.42 (d, 2H, J=8 Hz). MS (DCl/NH₃) m/e525 (M+H)⁺. Anal calcd for C₃₀H₄₀N₂O₆.1.25 TFA: C, 58.51; H, 6.23; N,4.20. Found: C, 58.52; H,. 6.28; N, 4.33.

EXAMPLE 102trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-(tert-butyloxycarbonylmethyl)amino)ethyl]pyrrolidine-3-carboxylicAcid

The title compound was prepared by the methods described in Example 61,but substituting propylamine for methylamine in Example 61B and t-butylbromoacetate for isobutyryl chloride in Example 61C. The crude productwas purified by trituration with 1:1 diethyl ether-hexane. The resultingsolid was dissolved in CH₃CN and water and lyophilized to give theproduct as a white solid. ¹H NMR (CDCl₃, 300 MHz) δ 0.82 (t, 3H, J=8Hz), 1.18 (m, 2H), 1.19 (s, 9H), 2.12 (m, 1H), 2.46 (m, 2H), 2.70 (m,3H), 2.85 (m, 2H), 3.20 (s, 2H), 3.40 (dd, 1H, J=2,8 Hz), 3.50 (dt, 1H,J=2,8 Hz), 3.62 (d, 1H, J=8 Hz), 3.78 (s, 3H), 5.95 (s, 2H), 6.72 (d,1H, J=8 Hz), 6.84 (m, 1H), 6.85 (d, 2H, J=8 Hz), 7.05 (s, 1H), 7.16 (d,2H, J=8 Hz). MS (DCl/NH₃) m/e 541 (M+H)⁺. Anal calcd for C₃₀H₄₀N₂O₇.1.0H₂O: C, 64.50; H, 7.58; N, 5.01. Found: C, 64.75; H, 7.35; N, 4.86.

EXAMPLE 103trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-(n-propylaminocarbonylmethyl)amino)ethyl]pyrrolidine-3-carboxylicAcid

The title compound was prepared by the methods described in Example 61,but substituting propylamine for methylamine in Example 61B and N-propylbromoacetamide for isobutyryl chloride in Example 61C. The crude productwas purified by preparative HPLC (Vydac μC18) eluting with a 10-70%gradient of CH₃CN in 0.1% TFA. The desired fractions were lyophilized togive the product as a white solid. ¹H NMR (CDCl₃, 300 MHz) δ 0.78 (t,3H, J=8 Hz), 0.88 (t, 3H, J=8 Hz), 1.45 (m, 2H), 1.48 (m, 3H, J=8 Hz),2.55-2.7 (m, 2H), 2.90 (m, 1H), 3.04 (m, 1H), 3.15 (m, 3H), 3.28 (t, 1H,J=8 Hz), 3.45 (t, 1H, J=8 Hz), 3.60 (m, 2H), 3.70 (d, 2H, J=8Hz), 3.75(m, 1H), 3.80 (s, 3H), 4.25 (d, 1H, J=8Hz), 5.95 (s, 2H), 6.75(d, 1H,J=8 Hz), 6.86 (dt, 1H, J=1,8Hz), 6.88 (d, 2H, J=8Hz), 7.04 (d, 1H, J=1Hz), 7.40 (d, 2H, J=8 Hz). MS (DCl/NH₃) m/e 526 (M+H)⁺. Anal calcd forC₂₉H₃₉N₃O₆.1.85 TFA: C, 53.32; H, 5.59; N, 5.70. Found: C, 53.45; H,5.62; N, 5.63.

EXAMPLE 104trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-(4-methoxyphenoxycarbonyl)amino)ethyl]pyrrolidine-3-carboxylicAcid

The title compound was prepared by the methods described in Example 61,but substituting propylamine for methylamine in Example 61B and4-methoxyphenylchloroformate for isobutyryl chloride in Example 61C. Thecrude product was purified by trituration with 1:1 diethyl ether-hexane.The resulting solid was dissolved in CH₃CN and water and lyophilized togive the product as a while solid. ¹H NMR (CD₃OD, 300 MHz) mixture ofrotamers δ 0.88 (m,3H), 1.57 (m, 2H), 2.45 (br s) and 2.60 (br s, totalof 1H), 2.90-3.15 (m, 4H), 3.42-3.7 (m, 5H), 3.78 (s, 3H), 3.80 (s, 3H),3.85 (m) and 4.0 (m, total of 1H), 5.95 (s) and 5.98 (s, total of 2H),6.63(m, 1H), 6.72 (d, 1H, J=8 Hz), 6.81 (m, 2H), 6.93 (m, 5H), 7.40 (m,2H). MS (DCl/NH₃) m/e 577 (M+H)⁺. Anal calcd for C₃₂H₃₆N₂O₈.1.0 H₂O: C,64.63; H, 6.44; N, 4.71. Found: C, 64.70; H, 6.38; N, 4.63.

EXAMPLE 105trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-(4-methoxybenzoyl)amino)ethyl]pyrrolidine-3-carboxylicAcid

The title compound was prepared by the methods described in Example 61,but substituting propylamine for methylamine in Example 61B and anisoylchloride for isobutyryl. chloride in Example 61C. The crude product waspurified by trituration with 1:1 diethyl ether-hexane. The resultingsolid was dissolved in CH₃CN and water and lyophilized to give theproduct as a white solid. ¹H NMR (CDCl₃, 300 MHz) mixture of rotamers δ0.78 (m) and 0.98 (t, J=8 Hz) total of 3H, 1.47 (m) and 1.52 (q, J=8 Hz)total of 2H, 2.25 (br s, 1H), 2.78 (br s, 1H), 2.90 (br t, 2H),3.12-3.68 (m, 7H), 3.80 (s, 3H), 3.82 (s, 3H), 5.94 (s, 2H), 6.75(d, 1H,J=8 Hz), 6.83 (m, 5H), 6.94 (m, 1H), 7.22 (m, 4H). MS (FAB) m/e 561(M+H)⁺. Anal calcd for C₃₂H₃₆N₂O₇.0.75 H₂O: C, 66.94; H, 6.58; N, 4.88.Found: C, 67.00; H, 6.38; N, 4.59.

EXAMPLE 106trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-benzoylamino)ethyl]pyrrolidine-3-carboxylicAcid

The title compound was prepared by the methods described in Example 61,but substituting propylamine for methylamine in Example 61B and benzoylchloride for isobutyryl chloride in Example 61C. The crude product waspurified by trituration with 1:1 diethyl ether-hexane. The resultingsolid was dissolved in CH₃CN and water and lyophilized to give theproduct as a white solid. ¹H NMR (CDCl₃, 300 MHz) mixture of rotamers δ0.65 and 0.9 (m, total of 3H), 1.4 and 1.55 (m, total of 2H), 2.05 and2.15 (m, total of 1H), 2.6-3.6 (m, 8H), 5.92 (s, 2H), 6.70(d, 1H, J=8Hz), 6.82 (m, 4H), 7.2-7.4 (m, 6H). MS (DCl/NH₃) m/e 531 (M+H)⁺. Analcalcd for C₃₁H₃₄N₂O₆.0.3 H₂O: C, 69.46; H, 6.51; N, 5.23. Found: C,69.48; H, 6.19; N, 4.84.

EXAMPLE 107trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-benzyloxycarbonylamino)ethyl]pyrrolidine-3-carboxylicAcid

The title compound was prepared by the methods described in Example 61,but substituting propylamine for methylamine in Example 61B and benzylchloroformate for isobutyryl chloride in Example 61C. The crude productwas purified by preparative HPLC (Vydac μC18) eluting with a 10-70%gradient of CH₃CN in 0.1% TFA. The desired fractions were lyophilized togive the product as a white solid. ¹H NMR (CDCl₃, 300 MHz) δ 0.8 (m, 3H)1.45 (m, 2H), 2.20 (br m, 1H), 2.75 (m, 1H), 2.93 (m, 1H), 3.15 (m, 2H),3.32 (m, 3H), 3.52 (m, 2H), 3.66 (m, 1H), 3.78 (s, 3H), 5.00 (m, 2H),5.94 (s, 2H), 6.72(d, 1H, J=8 Hz), 6.82 (m, 3H), 7.0 (br d, 1H, J=15Hz), 7.2 (s, 4H), 7.30 (m, 3H). MS (FAB) m/e 561 (M+H)⁺. Anal calcd forC₃₂H₃₆N₂O₇.1.0 TFA: C, 60.53; H, 5.53; N, 4.15. Found: C, 60.66; H,5.34; N, 4.28.

EXAMPLE 108trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-(4-methoxybenzyloxycarbonyl)amino)ethyl]pyrrolidine-3-carboxylicAcid

The title compound is prepared by the methods described in Example 61,substituting propylamine for methylamine in Example 61B and4-methoxybenzyl chloroformate for isobutyryl chloride in Example 61C.

EXAMPLE 109trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-butyl-N-ethoxycarbonylamino)ethyl]pyrrolidine-3-carboxylicAcid

The title compound was prepared by the methods described in Example 61,but substituting butylamine for methylamine in Example 61B and ethylchloroformate for isobutyryl chloride in Example 61C. The crude productwas purified by preparative HPLC (Vydac μC18) eluting with a 10-70%gradient of CH₃CN in 0.1% TFA. The desired fractions were lyophilized togive the product as a white solid. ¹H NMR (CDCl₃, 300 MHz) δ 0.82 (t,3H, J=8 Hz), 1.20 (m, 5H), 1.34 (m, 2H), 3.08 (m, 2H), 3.17 (m, 2H),3.52 (m, 2H), 3.75 (m, 2H), 3.78 (s, 3H), 4.06 (q, 2H, J=8 Hz), 4.35 (brs, 1H), 5.94 (s, 2H), 6.76 (d, 1H, J=8 Hz), 6.92 (d, 2H, J=8 Hz), 7.03(br s, 1H), 7.17 (br s, 1H), 7.7 (br s, 2H). MS (FAB) m/e 513 (M+H)⁺.Anal calcd for C₂₈H₃₆N₂O₇.0.5 TFA: C, 61.15; H, 6.46; N, 4.92. Found: C,60.99; H, 6.80; N, 4.93.

EXAMPLE 110trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-butyl-N-propoxycarbonylamino)ethyl]pyrrolidine-3-carboxylicAcid

The title compound was prepared by the methods described in Example 61,but substituting butylamine for methylamine in Example 61B and propylchloroformate for isobutyryl chloride in Example 61C. The crude productwas purified by trituration with 1:1 diethyl ether-hexane. The resultingsolid was dissolved in CH₃CN and water and lyophilized to give theproduct as a white solid. ¹H NMR (CDCl₃, 300 MHz) δ 0.80 (br s, 1H),0.85 (t, 3H, J=8 Hz), 0.92 (br s, 1H), 1.22 (m, 3H), 1.40 (m, 3H), 1.62(br m, 1H), 2.15 (br s, 1H), 2.72 (m, 1H), 2.87 (m, 1H), 3.1-3.45 (m,5H), 3.55 (m, 1H), 3.64 (d, 1H, J=8 Hz), 3.79 (s, 3H), 3.88 (br s, 1H),3.97 (br s, 1H), 5.95 (s, 2H), 6.73 (d, 1H, J=8 Hz), 6.85 (m, 3H, 7.0(s, 1H), 7.30 (d, 2H, J=8 Hz). MS (FAB) m/e 527 (M+H)⁺. Anal calcd forC₂₉H₃₈N₂O₇.0.15 H₂O: C, 65.80; H, 7.29; N, 5.29. Found: C, 65.79; H,7.30; N, 5.21.

EXAMPLE 111trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-propoxycarbonylamino)ethyl]pyrrolidine-3-carboxylicAcid

The title compound was prepared by the methods described in Example 61,but substituting propylamine for methylamine in Example 61B and propylchloroformate for isobutyryl chloride in Example 61C. The crude productwas purified by trituration with 1:1 diethyl ether-hexane. The resultingsolid was dissolved in CH₃CN and water and lyophilized to give theproduct as a white solid. ¹H NMR (CDCl₃, 300 MHz) δ 0.80 (t, 3H, J=8Hz), 093 (m, 3H), 1.43 (m, 3H), 1.62 (m, 1H), 2.15 (br s, 1H), 2.68-3.45(m, 8H), 3.54 (m, 1H), 3.66 (m, 1H), 3.78 (s, 3H), 3.94 (m, 2H), 5.94(s, 2H), 6.72 (d, 1H, J=8 Hz), 6.82 (m, 1H), 6.84 (d, 2H, J=8 Hz), 7.00(br s, 1H), 7.33 (m, 2H). MS (DCl/NH₃) m/e 513 (M+H)⁺. Anal calcd forC₂₈H₃₆N₂O₇.0.15 H₂O: C, 65.26; H, 7.10; N, 5.44. Found: C, 65.22; H,6.74; N, 5.06.

EXAMPLE 112trans,trans-1-(N,N-Di(n-Butyl)aminocarbonylmethyl)-2,4-di(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

Ethyl (3,4-methylenedioxybenzoyl)acetate, prepared by the method ofKrapcho et al., Org. Syn. 47, 20 (1967) starting with3,4-methylenedioxyacetophenone instead of 4-methoxyacetophenone, wasreacted by the procedures described in Example 1 to give the titlecompound as a white solid. m.p. 58-60° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.87(quintet, J=6 Hz, 6H), 1.12 (sextet, J=6 Hz, 2H), 1.24-1.51 (m, 6H),2.80 (d, J=13 Hz, 1H), 2.94-3.12 (m, 4H), 3.28-3.50 (m, 4H), 3.58-3.62(m, 1H), 3.78 (d, J=9 Hz, 1H), 5.95 (s, 4H), 6.73 (dd, J=8 Hz, 3 Hz,2H), 6.84-6.89 (m, 2H), 6.92 (d, J=1 Hz, 1H), 7.01 (d, H=1 Hz, 1H). MS(DCl/NH₃) m/e 525 (M+H)⁺.

EXAMPLE 113trans,trans-1-(2-(N-(n-Butyl)-N-propylsulfonylamino)ethyl)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 66, the title compound wasprepared as a white solid. m.p. 64-65° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.83(t, J=7 Hz, 3H), 0.98 (t, J=7 Hz, 3H), 1.12-1.25 (m, 2H), 1.32-1.41 (m,2H), 1.75 (sextet, J=7 Hz, 2H), 2.23-2.31 (m, 2H), 2.72-3.32 (m, 8H),3.43 (dd, J=9 Hz, 3 Hz, 1H), 3.53-3.59 (m, 1H), 3.65 (d, J=9 Hz, 1H),3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=8 Hz, 1H), 6.83 (dd, J=8 Hz, 1Hz, 1H), 6.88 (d, J=9 Hz, 2H), 7.02 (d, J=1 Hz, 1H), 7.33 (d, J=9 Hz,2H). MS (DCl/NH₃) m/e 547 (M+H)⁺.

EXAMPLE 114trans,trans-1-(N,N-Di(n-Butyl)aminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

Using the procedures described in Examples 28 and 43, the title compoundwas prepared as a white solid. m.p. 74-76° C. ¹H NMR (CDCl₃, 300 MHz) δ0.80 (t, J=6 Hz, 3H), 0.88 (t, J=8 Hz, 3H), 1.08 (sextet, J=8 Hz, 2H),1.21-1.48 (m, 6H), 2.75 (d, J=12 Hz, 1H), 2.95-3.09 (m, 4H), 3.26-3.59(m, 5H), 3.75 (d, J=9 Hz, 1H), 3.79 (s, 3H), 4.28 (s, 4H), 6.78 (d, J=9Hz, 1H), 6.85 (d, J=9 Hz, 2H), 6.91 (d,d, J=3 Hz, 9 Hz, 1H), 6.98 (d,J=3 Hz, 1H), 7.32 (d, J=9 Hz, 2H). MS (DCl/NH₃) m/e 525 (M+H)⁺.

EXAMPLE 115trans,trans-1-(2-(N-Propyl-N-propylsulfonylamino)ethyl)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 66, the title compound wasprepared as a white solid. m.p. 72-73° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.79(t, J=8 Hz, 3H), 0.98 (t, J=8 Hz, 3H), 1.43 (sextet, J=8 Hz, 2H), 1.75(sextet, J=8 Hz, 2H), 2.22-2.32 (m, 1H), 2.69-3.32 (m, 9H), 3.42 (dd,J=3 Hz, 12 Hz, 1H), 3.52-3.58 (m, 1H), 3.64 (d, J=12 Hz, 1H), 3.80 (s,3H), 5.95 (s, 2H), 6.73 (d, J=11 Hz, 1H), 6.83 (dd, J=1 Hz, 11 Hz, 1H),6.87 (d, J=11 Hz, 2H), 7.0 (d, J=2 Hz, 1H), 7.32 (d, J=11 Hz, 2H). MS(DCl/NH₃) m/e 533 (M+H)⁺.

EXAMPLE 116trans,trans-1-(2-(N-Butyl-N-butylsulfonylamino)ethyl)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 66, the title compound wasprepared as a white solid. m.p. 62-63° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.82(t, J=6 Hz, 3H), 0.91)t, J=6 Hz, 3H), 1.20 (sextet, J=6 Hz, 2H),1.33-1.42 (m, 4H), 1.68 (quintet, J=6 Hz, 3H), 2.23-2.32 (m, 1H),2.70-3.28 (m, 9H), 3.41 (d, J=8 Hz, 1H), 3.52-3.58 (m, 1H), 3.65 (d, J=8Hz, 1H), 3.79 (s, 3H), 5.95 (s, 2H), 6.72 (d, J=8 Hz, 1H), 6.82 (d, J=8Hz, 1H), 6.87 (d, J=8 Hz, 2H), 7.01 (s, 1H), 7.32 (d, J=8 Hz, 2H). MS(DCl/NH₃) m/e 561 (M+H)⁺.

EXAMPLE 117trans,trans-1-(2-(N,N-Di(n-Butyl)aminocarbonylmethyl)-2-(4-methoxymethoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

4-Hydroxyacetophenone was treated with chloromethyl methyl ether andtriethylamine in THF at room temperature to give ethyl4-methoxymethoxybenzoylacetate which was treated by the proceduresdescribed in Example 1 to afford the title compound as a white solid.m.p. 48-49° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.81 (t, J=7 Hz, 3H), 0.88 (t,J=7 Hz, 3H), 1.06 (sextet, J=7 Hz, 2H), 1.20-1.35 (m, 4H), 1.44(quintet, J=7 Hz, 2H), 2.75 (d, J=12 Hz, 1H), 2.94-3.10 (m, 4H),3.25-3.35 (m, 1H), 3.40 (d, J=12 Hz, 1H), 3.43-3.52 (m, 2H), 3.47 (s,3H), 3.55-3.62 (m, 1H), 3.77 (d, J=9 Hz, 1H), 5.15 (s, 2H), 5.94 (m,2H), 6.73 (d, J=8 Hz, 1H), 6.86 (dd, J=1 Hz, 8 Hz, 1H), 7.0 (d, J=8 Hz,2H), 7.04 (d, J=1 Hz, 1H), 7.32 (d, J=8 Hz, 2H). MS (DCl/NH₃) m/e 541(M+H)⁺.

EXAMPLE 118trans,trans-1-(2-(N,N-Di(n-Butyl)aminocarbonylmethyl)-2-(4-hydroxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid Hydrochloride Salt

The compound resulting from Example 116 was treated with concentratedHCl in 1:1 THF-isopropanol to give the title compound as a white solid.m.p. 211-212° C. ¹H NMR (CD₃OD, 300 MHz) δ 0.90 (t, J=8 Hz, 6H),1.12-1.27 (m, 6H), 1.36-1.45 (m, 2H), 3.04 (bs, 1H), 3.14-3.35 (t, J=9Hz, 1H), 3.90 (bs, 3H), 4.17 (d, J=15 Hz, 1H), 5.96 (s, 2H), 6.82-6.93(m, 4H), 7.03 (d, J=1 Hz, 1H), 7.42 (bs, 2H). MS (DCl/NH₃) m/e 497(M+H)⁺.

EXAMPLE 119trans,trans-1-(2-(N-Isobutyl-N-propylsulfonylamino)ethyl)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 66, the title compound wasprepared as a white solid. m.p. 73-74° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.80(d, J=6 Hz, 6H), 0.98 (t, J=8 Hz, 3H), 1.62 (sextet, J=6 Hz, 1H), 1.74(sextet, J=8 Hz, 2H), 2.23-2.34 (m, 1H), 2.68-2.98 (m, 7H), 3.08-3.18(m, 1H), 3.26-3.42 (m, 2H), 3.52-3.58 (m, 1H), 3.65 (d, J=9 Hz, 1H),3.80 (s, 3H), 5.90 (s, 2H), 6.74 (d, J=8 Hz, 1H), 6.82 (d, J=8 Hz, 1H),6.86 (d, J=8 Hz, 2H), 6.98 (d, J=1 Hz, 1H), 7.33 (d, J=8 Hz, 2H). MS(DCl/NH₃) m/e 547 (M+H)⁺.

EXAMPLE 120trans,trans-1-(2-(N-Benzenesulfonyl-N-propylamino)-ethyl)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 66, the title compound wasprepared as a white solid. m.p. 89-91° C. ¹H-NMR (CDCl₃, 300 MHz) δ 0.74(t, J=6 Hz, 3H), 1.33 (sextet, J=6 Hz, 2H), 2.20-2.30 (m, 1H), 2.62-2.72(m, 1H), 2.85-3.05 (m, 4H), 3.12-3.22 (m, 1H), 3.38 (dd, J=3 Hz, 9 Hz,1H), 3.49-3.57 (m, 1H), 3.62 (d, J=9 Hz, 1H), 3.82 (s, 3H), 5.96 (s,2H), 6.73 (d, J=8 Hz, 1H), 6.84 (dd, J=1 Hz, 8 Hz, 1H), 6.85 (d, J=9 Hz,2H), 7.02 (d, J=1 Hz, 1H), 7.28 (d, J=9 Hz, 2H), 7.39-7.54 (m, 3H), 7.70(d, J=7 Hz, 2H). MS (DCl/NH₃) m/e 567 (M+H)⁺.

EXAMPLE 121trans,trans-1-(2-(N-(4-Methoxybenzenesulfonyl)-N-propylamino)ethyl)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 66, the title compound wasprepared as a white solid. m.p. 96-97° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.73(t, J=7 Hz, 3H), 1.34 (sextet, J=7 Hz, 2H), 2.20-2.30 (m, 1H), 2.62-2.71(m, 1H), 2.82-3.03 (m, 4H), 3.08-3.18 (m, 2H), 3.38 (dd, J=3 Hz, 9 Hz,1H), 3.48-3.56 (m, 1H), 3.62 (d, J=9 Hz, 1H), 3.81 (s, 3H), 3.86 (s,3H), 5.95 (s, 2H), 6.73 (d, J=8 Hz, 1H), 6.81-6.89 (m, 5H), 7.01 (d, J=1Hz, 1H), 7.28 (d, J=8 Hz, 2H), 7.62 (d, J=8 Hz, 2H). MS (DCl/NH₃) m/e597 (M+H)⁺.

EXAMPLE 122trans,trans-1-(N,N-Di(n-Butyl)aminocarbonylmethyl)-2-(2-methoxyethoxy-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

2-Hydroxy-5-methoxyacetophenone was treated with sodium hydride andbromoethyl methyl ether in THF at 70° C. to provide ethyl2-methoxyethoxy-4-methoxybenzoylacetate which was treated by theprocedures described in Example 1 to provide the title compound as awhite solid. m.p. 63-65° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.84 (t, J=7 Hz,3H), 0.89 (t, J=7 Hz, 3H), 1.16 (sextet, J=7 Hz, 2H), 1.28 (sextet, J=7Hz, 2H), 1.45-1.52 (m, 4H), 2.87-2.94 (m, 2H), 3.00-3.16 (m, 3H),3.26-3.36 (m, 2H), 3.43 (s, 3H), 3.47-3.54 (m, 3H), 3.66-3.72 (m, 2H),3.78 (s, 3H), 3.76-3.84 (m, 1H), 4.02-4.10 (m, 2H), 4.25 (d, J=9 Hz,1H), 5.92 (s, 2H), 6.40 (d, J=2 Hz, 1H), 6.52 (dd, J=2 Hz, 9 Hz, 1H),6.70 (d, J=8 Hz, 1H), 6.83 (dd, J=1 Hz, 8 Hz, 1H), 5.98 (d, J=2 Hz, 1H),7.53 (d, J=9 Hz, 1H). MS (DCl/NH₃) m/e 585 (M+H)⁺.

EXAMPLE 123trans,trans-1-(2-(N-Propyl-N-(2,4-dimethylbenzenesulfonyl)amino)ethyl)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 66, the title compound wasprepared as a white solid. m.p. 88-90° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.69(t, J=7 Hz, 3H), 1.32 (sextet, J=7 Hz, 2H), 2.12-2.20 (m, 1H), 2.32 (s,3H), 2.47 (s, 3H), 2.62-2.69 (m, 1H), 2.78 (t, J=9 Hz, 1H), 2.89 (dd,J=8 Hz, 1H), 3.02 (sextet, J=9 Hz, 2H), 3.15-3.32 (m, 3H), 3.46-3.55 (m,1H), 3.60 (d, J=9 Hz, 1H), 3.82 (s, 3H), 5.96 (s, 2H), 6.72 (d, J=7 Hz,1H), 6.80 (dd, J=1 Hz, 9 Hz, 1H), 6.86 (d, J=9 Hz, 2H), 6.97 (d, J=1 Hz,1H), 7.03 (bs, 2H), 7.29 (d, J=9 Hz, 1H). MS (DCl/NH₃) m/e 595 (M+H)⁺.

EXAMPLE 124trans,trans-1-(2-(N-Propyl-N-(3-chloropropylsulfonyl)amino)ethyl)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 66, the title compound wasprepared as a white solid. m.p. 75-76° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.80(t, J=7 Hz, 3H), 1.45 (sextet, J=7 Hz, 2H), 2.15-2.31 (m, 3H), 2.70-2.80(m, 1H), 2.85-3.10 (m, 6H), 3.23-3.31 (m, 2H), 3.43 (bd, J=9 Hz, 1H),3.55-3.66 (m, 4H), 3.81 (s, 3H), 5.94 (s, 2H), 6.73 (d, J=8 Hz, 1H),6.82 (d, J=8 Hz, 1H), 6.86 (d, J=8 Hz, 2H), 7.00 (s, 1H), 7.33 (d, J=8Hz, 2H). MS (DCl/NH₃) m/e 567 (M+H)⁺.

EXAMPLE 125trans,trans-1-(2-(N-Propyl-N-(2-methoxyethylsulfonyl)amino)ethyl)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 66,trans,trans-1-(2-(N-Propyl-N-(vinylsulfonyl)amino)ethyl)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicacid was prepared. Ester hydrolysis using aqueous sodium hydroxide inmethanol afforded the title compound as a white solid. m.p. 62-64° C. ¹HNMR (CDCl₃, 300 MHz) δ 0.78 (t, J=7 Hz, 3H), 1.42 (sextet, J=7 Hz, 2H),2.23-2.32 (m, 1H), 2.72-2.79 (m, 1H), 2.86-3.05 (m, 4H), 3.10-3.27 (m,4H), 3.32 (s, 3H), 3.43 (dd, J=3 Hz, 9 Hz, 1H), 3.53-3.58 (m, 1H), 3.65(d, J=9 Hz, 1H), 3.69 (t, J=6 Hz, 2H), 3.80 (s, 3H), 5.94 (s, 2H), 6.73(d, J=8 Hz, 1H), 6.82 (dd, J=1 Hz, 8 Hz, 1H), 6.87 (d, J=8 Hz, 2H), 7.02(d, J=1 Hz, 1H), 7.33 (d, J=8 Hz, 2H). MS (DCl/NH₃) m/e 549 (M+H)⁺.

EXAMPLE 126trans,trans-1-(2-(N-Propyl-N-(2-ethoxyethylsulfonyl)amino)ethyl)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 66, the title compound wasprepared as a white solid. m.p. 58-60° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.78(t, J=7 Hz, 3H), 1.18 (t, J=7 Hz, 3H), 1.43 (sextet, J=7 Hz, 2H),2.24-2.33 (m, 1H), 2.70-2.80 (m, 1H), 2.87-3.05 (m, 4H), 3.13-3.20 (m,2H), 3.22-3.32 (m, 2H), 3.42 (dd, J=2 Hz, 9 Hz, 1H), 3.46 (q, J=7 Hz,2H), 3.52-3.58 (m, 1H), 3.65 (d J=9 Hz, 1H), 3.72 (t, J=6 Hz, 2H), 3.80(s, 3H), 5.95 (s, 2H), 6.73 (d, J=7 Hz, 1H), 6.83 (dd, J=1 Hz, 7 Hz,1H), 6.87 (d, J=8 Hz, 2H), 7.00 (d, J=1 Hz, 1H), 7.32 (d, J=8 Hz, 2H).MS (DCl/NH₃) m/e 563 (M+H)⁺.

EXAMPLE 127trans,trans-1-(2-(N-Propyl-N-(5-dimethylamino-1-naphthylsulfonyl)amino)ethyl)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 66, the title compound wasprepared as a yellow solid. m.p. 102-104° C. ¹H NMR (CDCl₃, 300 MHz) δ0.62 (t, J=7 Hz, 3H), 1.28 (sextet, J=7 Hz, 2H), 2.12-2.20 (m, 1H), 2.78(t, J=9 Hz, 1H), 2.88 (s, 6H), 2.72-2.89 (m, 1H), 3.05-3.12 (m, 2H),3.26-3.45 (m, 3H), 3.45-3.52 (m, 1H), 3.58 (d, J=9 Hz, 1H), 6.97 (d, J=1Hz, 1H), 7.13 (d, J=7 Hz, 1H), 7.26 (d, J=8 Hz, 1H), 7.42-7.50 (m, 2H),8.08 (dd, J=1 Hz, 7 Hz, 1H), 8.20 (d, J=8 Hz, 1H), 8.48 (d, J=8 Hz, 1H).MS (DCl/NH₃) m/e 660 (M+H)⁺.

EXAMPLE 128trans,trans-1-(2-(N-Propyl-N-(ethylsulfonyl)amino)ethyl)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 66, the title compound wasprepared as a white solid. m.p. 70-72° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.79(t, J=8 Hz, 3H), 1.28 (t, J=7 Hz, 3H), 1.43 (q, J=8 Hz, 2H), 2.22-2.30(m, 1H), 2.71-2.80 (m, 1H), 2.82-3.10 (m, 6H), 3.18-3.32 (m, 2H), 3.43(dd, J=3 Hz, 9 Hz, 1H), 3.53-3.60 (m, 1H), 3.65 (d, J=9 Hz, 1H), 3.80(s, 3H), 5.96 (s, 2H), 6.73 (d, J=7 Hz, 1H), 6.82 (dd, J=1 Hz, 7 Hz,1H), 6.88 (d, J=8 Hz, 2H), 7.00 (d, J=1 Hz, 1H), 7.32 (d, J=8 Hz, 2H).MS (DCl/NH₃) m/e 519 (M+H)⁺.

EXAMPLE 129trans,trans-1-(2-(N-Propyl-N-(4-methylbenzenesulfonyl)amino)ethyl)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 66, the title compound wasprepared as a white solid. m.p. 78-79° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.73(t, J=7 Hz, 3H), 1.33 (sextet, J=7 Hz, 2H), 2.20-2.30 (m, 1H), 2.40 (s,3H), 2.61-2.72 (m, 1H), 2.83-3.05 (m, 4H), 3.08-3.19 (m, 2H), 3.48 (dd,J=3 Hz, 9 Hz, 1H), 3.49-3.57 (m, 1H), 3.62 (d, J=9 Hz, 1H), 3.81 (s,3H), 5.95 (s, 2H), 6.73 (d, J=8 Hz, 1H), 6.82 (d, J=8 Hz, 1H), 6.87 (d,J=8 Hz, 2H), 7.00 (s, 1H), 7.21 (d, J=8 Hz, 2H), 7.29 (d, J=8 Hz, 2H),7.57 (d, J=8 Hz, 2H). MS (DCl/NH₃) m/e 581 (M+H)⁺.

EXAMPLE 130trans,trans-1-(N,N-Di(n-Butyl)aminocarbonylmethyl)-2-(3-pyridyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

Methyl nicotinoyl acetate was prepared by the method of Wenkert, et al.,J. Org. Chem. 48: 5006 (1983) and treated by the procedures described inExample 1 to provide the title compound as a white solid. m.p. 167-168°C. ¹H NMR (CDCl₃, 300 MHz) δ 0.82 (t, J=7 Hz, 3H), 0.89 (t, J=7 Hz, 3H),1.14 (sextet, J=7 Hz, 2H), 1.23-1.48 (m, 6H), 2.86-3.20 (m, 6H),3.34-3.43 (m, 2H), 3.57 (dd, J=3 Hz, 9 Hz, 1H), 3.75-3.83 (m, 1H), 4.08(d, J=9 Hz, 1H), 5.93 (s, 2H), 6.73 (d, J=8 Hz, 1H), 6.90 (dd, J=2 Hz, 8Hz, 1H), 7.03 (d, J=2 Hz, 1H), 7.38 (dd, J=4 Hz, 8 Hz, 1H), 8.04 (d, J=8Hz, 1H), 8.48 (dd, J=2 Hz, 4 Hz, 2H). MS (DCl/NH₃) m/e 482 (M+H)⁺.

EXAMPLE 131trans,trans-1-(2-(N-Propyl-N-(n-butylsulfonyl)amino)ethyl)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 66, the title compound wasprepared as a white solid. m.p. 65-66° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.78(t, J=7 Hz, 3H), 0.92 (t, J=7 Hz, 3H), 1.31-1.46 (m, 4H), 1.68 (quintet,J=7 Hz, 2H), 2.21-2.32 (m, 1H), 2.70-3.08 (m, 7H), 3.12-3.23 (m, 2H),3.42 (dd, J=2 Hz, 9 Hz, 1H), 3.52-3.58 (m, 1H), 3.64 (d, J=9 Hz, 1H),3.80 (s, 3H), 5.96 (s, 2H), 6.72 (d, J=7 Hz, 1H), 6.83 (dd, J=1 Hz, 7Hz, 1H), 6.86 (d, J=8 Hz, 2H), 7.00 (d, J=1 Hz, 1H), 7.32 (d, J=8 Hz,2H). MS (DCl/NH₃) m/e 547 (M+H)⁺.

EXAMPLE 132trans,trans-1-(2-(N-Propyl-N-(4-chlorobenzenesulfonyl)amino)ethyl)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 66, the title compound wasprepared as a white solid. m.p. 105-106° C. ¹H NMR (CDCl₃, 300 MHz) δ0.72 (t, J=7 Hz, 3H), 1.34 (sextet, J=7 Hzm 2H), 2.56-2.62 (m, 1H),2.78-2.86 (m, 1H), 2.96-3.03 (m, 3H), 3.13-3.26 (m, 3H), 3.51 (dd, J=5Hz, 9 Hz, 1H), 3.62-3.68 (m, 1H), 3.80 (s, 3H), 3.94 (d, J=9 Hz, 1H),5.92 (s, 2H), 6.75 (d, J=8 Hz, 1H), 6.84 (dd, J=2 Hz, 8 Hz, 1H), 6.94(d, J=8 Hz, 2H), 6.98 (d, J=2 Hz, 1H), 7.36 (d, J=8 Hz, 1H), 7.49 (d,J=8 Hz, 1H), 7.68 (d, J=8 Hz, 1H). MS (DCl/NH₃) m/e 601 (M+H)⁺.

EXAMPLE 133trans,trans-1-(2-(N-Propyl-N-(benzylsulfonyl)amino)ethyl)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 66, the title compound wasprepared as a white solid. m.p. 88-89° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.72(t, J=7 Hz, 3H), 1.32 (sextet, J=7 Hz, 2H), 2.06-2.16 (m, 1H), 2.56-2.67(m, 1H), 2.75-3.10 (m, 6H), 3.30 (dd, J=2 Hz, 9 Hz, 1H), 5.95 (s, 2H),6.73 (d, J=7 Hz, 1H), 6.80 (dd, J=1 Hz, 7 Hz, 1H), 6.86 (d, J=8 Hz, 2H),6.97 (d, J=1 Hz, 1H), 7.27-7.35 (m, 7H). MS (DCl/NH₃) m/e 581 (M+H)⁺.

EXAMPLE 134trans,trans-1-(2-(N-Propyl-N-(4-fluorobenzenesulfonyl)amino)ethyl)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 66, the title compound wasprepared as a white solid. m.p. 91-93° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.73(t, J=7 Hz, 3H), 1.44 (sextet, J=7 Hz, 2H), 2.18-2.27 (m, 1H), 2.56-2.67(m, 1H), 2.78-2.87 (m, 2H), 2.97 (septet, J=8 Hz, 2H), 3.11-3.16 (m,2H), 3.33 (dd, J=2 Hz, 9 Hz, 1H), 3.43-3.50 (m, 1H), 3.57 (d, J=9 Hz,1H), 3.78 (s, 3H), 7.08 (t, J=8 Hz, 2H), 7.24 (d, J=8 Hz, 2H), 7.69 (dd,J=5 Hz, 8 Hz, 2H). MS (DCl/NH₃) m/e 585 (M+H)⁺.

EXAMPLE 135trans,trans-1-(N-Methyl-N-propylaminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(4-benzofuranyl)pyrrolidine-3-carboxylicAcid EXAMPLE 135A Benzofuran-4-carboxaldehyde

To a suspension of 60% sodium hydride in mineral oil (4.00 g, 100 mmol,1.25 eq) in DMF (60 mL) at 0° C. was added a solution of 3-bromophenol(13.8 g, 80 mmol) in DMF (5 mL). After 10 minutes, bromoacetaldehydediethyl acetal (14.9 mL, 96.6 mmol, 1.24 eq) was added, and theresultant mixture then heated at 120° C. for 2.5 hours. The mixture wascooled to room temperature and was poured into water, and extracted oncewith ether. The organic solution was dried over MgSO₄, filtered,evaporated and vacuum distilled to yield a colorless liquid (17.1 g,74%). b.p. 160-163° C. at 0.4 mm Hg.

To warm polyphosphoric acid (15.3 g) was added a solution of the abovecompound (17.1 g, 59.3 mmol) in benzene (50 mL). The resultant mixturewas heated under reflux with vigorous stirring for 4 hours, after whichtime the benzene layer was carefully decanted off, and the lower layerwashed once with hexanes. The combined organic solutions wereconcentrated in vacuo, and then vacuum distilled to yield a colorlessliquid (8.13 g, 70%). b.p. 62-72° C. at 0.6 mm Hg.

To a solution of the above compounds (8.11 g, 41.5 mmol) in ether (80mL) at −78° C. was added 1.7 M t-butyllithium (48.8 mL, 83 mmol, 2 eq)such that the temperature did not exceed −70° C. After stirring for 15minutes, a solution of DMF (6.5 mL, 83 mmol, 2 eq) in ether (20 mL) wasadded, and the mixture allowed to warm to room temperature over 2 hours.The mixture was poured into water and the phases separated. The organicsolution was dried over MgSO₄ and concentated in vacuo. The residue waspurified by flash chromatography on silica gel eluting with 10% ether inhexanes to yield benzofuran-6-carboxaldehyde (1.22 g) andbenzofuran-4-carboxaldehyde (1.86 g), both as colorless oils.

EXAMPLE 135Btrans,trans-1-(N-Methyl-N-propylaminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(4-benzofuranyl)pyrrolidine-3-carboxylicAcid

The title compound was prepared using the procedures described inExamples 1 and 49 substituting the compound resulting from Example 135Ain Example 49A for piperonal. ¹H NMR (300 MHz, CDCl₃) (minor rotamer) δ7.59 (1H, t, J=3 Hz), 7.4-7.2 (6H, m), 6.8 (2H, d, J=8 Hz), 4.03 (1H,m), 3.94 (1H, dd, J=8 Hz, 3 Hz), 3.77 (3H, s), 3.61 (1H, dd, J=8 Hz, 7 3Hz), 3.42 (1H, dd, J=1 Hz, 5 Hz), 3.40-2.90 (5H, m), 2.82 (2.81) (3H,s), 1.50 (2H, septet, J=7 Hz), 0.82 (0.75) (3H, t, J=7 Hz). MS (DCl/NH₃)m/e 451 (M+H)⁺. Anal.calc. for C₂₆H₃₀N₂O₅.AcOH: C, 65.87; H, 6.71; N,5.49. Found: C, 66.04; H, 6.42; N, 5.60. s

EXAMPLE 136trans,trans-1-(N-Methyl-N-propylaminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(6-benzofuranyl)pyrrolidine-3-carboxylicAcid

The title compound was prepared using the procedures described inExamples 1 and 49 substituting benzofuran-6-carboxaldehyde, prepared asdescribed in Example 135A, in Example 49A for piperonal. ¹H NMR (300MHz, CDCl₃) (minor rotamer) δ 7.65 (1H, bd), 7.60 (1H, d, J=2 Hz), 7.55(1H, d, J=8 Hz), 7.35 (3H, m), 6.85 (2H, dd, J=8 Hz, 3 Hz), 6.75 (1H,dd, J=3 Hz, 2 Hz), 3.83 (2H, m), 3.79 (3H, s), 3.60-3.0 (7H, m), 2.91(2.83) (s, 3H), 1.51 (2H, septet, J=7 Hz), 0.83 (0.78) (3H, t, J=7 Hz).MS (DCl/NH₃) m/e 451 (M+H)⁺. Anal.calc. for C₂₆H₃₀N₂O₅.0.5 H₂O: C,67.96; H, 6.80; N, 6.10. Found; C, 67.90; H, 6.71; N, 6.07.

EXAMPLE 137trans,trans-1-(N-Methyl-N-propylaminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(6-benzo-2,3-dihydrofuranyl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by catalytic hydrogenation (4atmospheres of H₂ in AcOH, followed by preparative hplc) of the compoundresulting from Example 136 ¹H NMR (300 MHz, CDCl₃) (minor rotamer) δ7.49 (7.47) (2H, d, J=8 Hz), 7.19 (1H, d, J=8 Hz), 7.00 (1H, m), 7.82(3H, m), 5.40 (1H, dd, J=11 Hz, 7 Hz), 4.58 (2H, t, J=8 Hz), 4.18 (1H,m), 4.10 (1H, m), 3.88 (1H, m), 3.79 (3H, s), 3.60 (1H, m), 3.35 (1H,m), 3.19 (2H, t, J=8 Hz), 3.00 (4H, m), 2.91 (2.78) (s, 3H), 1.53 (1.40)(2H, septet, J=7 Hz), 0.88 (0.78) (3H, t, J=7 Hz). MS (DCl/NH3) m/e 453(M+H)⁺. Anal.calc. for C₂₆H₃₂N₂O₅.1.25 TFA: C, 57.53; H, 5.63; N, 4.71.Found: C, 57.68; H, 5.68; N, 4.70.

EXAMPLE 138trans,trans-1-(N,N-Di(n-Butyl)aminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(4-benzofuranyl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting benzofuran-4-carboxaldehyde in Example 49A forpiperonal and substituting N,N-dibutyl bromoacetamide forN-methyl-N-propyl bromoacetamide. ¹H NMR (300 MHz, CDCl₃) δ 7.62 (1H, d,J=3 Hz), 7.39 (1H, dt, J=8 Hz, 2 Hz), 7.34 (3H, m), 7.26 (1H, d, J=2Hz), 7.23 (1H, d, J=8 Hz), 6.84 (2H, d, J=8 Hz), 4.02 (1H, ddd, J=8, 6Hz, 4 Hz), 3.89 (1H, d, J=9 Hz) 3.79 (3H, s), 3.67 (1H, dd, J=10 Hz, 3Hz), 3.44 (2H, m), 3.35-3.15 (3H, m), 3.00 (2H, m), 2.84 (1H, d, J=14Hz), 1.43 (3H, m), 1.23 (3H, m), 1.08 (2H, m), 0.87 (3H, t, J=7 Hz),0.82 (3H, t, J=7 Hz). MS (DCl/NH₃) m/e 507 (M+H)⁺. Anal.calc. forC₃₀H₃₈N₂O₅: C, 71.12; H, 7.56; N, 5.53. Found: C, 70.86; H, 7.45; N,5.24.

EXAMPLE 139trans,trans-1-(N,N-Di(n-Butyl)aminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(4-benzofuranyl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting benzofuran-5-carboxaldehyde, prepared by theprocedures described in Example 135A substituted 4-bromophenol for3-bromophenol, in Example 49A for piperonal and substituting N,N-dibutylbromoacetamide for N-methyl-N-propyl bromoacetamide. ¹H NMR (300 MHz,CDCl₃) δ 7.64 (1H, bd), 7.59 (1H, d, J=2 Hz), 7.43 (2H, m), 7.33 (2H, d,J=8 Hz), 6.85 (2H, d, J=8 Hz), 6.73 (1H, dd, J=3 Hz, 1 Hz), 3.82 (1H, d,J=11 Hz), 3.89 (1H, d, J=9 Hz) 3.79 (3H, s), 3.53 (1H, dd, J=10 Hz, 3Hz), 3.44 (2H, m), 3.30 (1H, m), 3.20-2.95 (5H, m), 2.82 (1H, d, J=14Hz), 1.43 (3H, m), 1.23 (3H, m), 1.08 (2H, m), 0.87 (3H, t, J=7 Hz),0.82 (3H, t, J=7 Hz). MS (DCl/NH₃) m/e 507 (M+H)⁺. Anal.calc. forC₃₀H₃₈N₂O₅: C, 71.12; H, 7.56; N, 5.53. Found: C, 70.73; H, 7.45; N,5.29.

EXAMPLE 140trans,trans-1-(N,N-Di(n-Butyl)aminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(6-benzofuranyl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting benzofuran-6-carboxaldehyde in Example 49A forpiperonal and substituting N,N-dibutyl bromoacetamide forN-methyl-N-propyl bromoacetamide. ¹H NMR (300 MHz, CDCl₃) δ 7.63 (1H,bd), 7.59 (1H, d, J=2 Hz), 7.53 (1H, d, J=8 Hz), 7.36 (3H, m), 6.85 (2H,d, J=8 Hz), 6.73 (1H, dd, J=3 Hz, 1 Hz), 3.82 (1H, d, J=11 Hz), 3.89(1H, d, J=9 Hz) 3.79 (3H, s), 3.53 (1H, dd, J=10 Hz, 3 Hz), 3.44 (2H,m), 3.30 (1H, m), 3.20-2.95 (5H, m), 2.80 (1H, d, J=14 Hz), 1.43 (3H,m), 1.23 (3H, m), 1.08 (2H, m), 0.87 (3H, t, J=7 Hz), 0.82 (3H, t, J=7Hz). MS (DCl/NH₃) m/e 507 (M+H)⁺. Anal.calc. for C₃₀H₃₈N₂O₅.0.75 H₂O: C,69.28; H, 7.65; N, 5.39. Found: C, 69.11; H, 7.33; N, 5.32.

EXAMPLE 141trans,trans-1-(N,N-Di(n-Butyl)aminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(6-benzo-2,3-dihydrofuranyl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by catalytic hydrogenation of thecompound resulting from Example 140 (4 atmospheres of H₂ in AcOH,followed by preparative hplc). ¹H NMR (300 MHz, CDCl₃) δ 7.40 (2H, d,J=8 Hz), 7.16 (1H, d, J=8 Hz), 6.97 (1H, dd, J=8 Hz, 2 Hz), 6.89 (3H,m), 5.90 (1H, bs) 4.57 (2H, t, J=9 Hz), 4.93 (2H, m), 3.80 (3H, s),3.70-3.58 (2H, m), 3.40 (1H, m), 3.30-2.90 (8H, m), 1.40 (2H, m), 1.29(3H, m), 1.08 (2H, m), 0.92 (3H, t, J=7 Hz), 0.82 (3H, t, J=7 Hz). MS(DCl/NH₃) m/e 509 (M+H)⁺. Anal.calc. for C₃₀H₄₀N₂O₅.0.85 TFA: C, 62.88;H, 6.80; N, 4.63. Found: C, 63.04; H, 6.66; N, 4.60.

EXAMPLE 142trans,trans-1-(N-Methyl-N-propylaminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(5-indanyl)pyrrolidine-3-carboxylicAcid EXAMPLE 142A Indane-5-carboxaldehyde

Indane-5-carboxaldehyde was prepared by formylation of indane under theconditions described for 2,3-dihydrobenzofuran in Example 52A. Theresultant mixture of 4- and 5-carboxaldehydes was purified as follows:to a 6:1 mixture of indane-4-carboxaldehyde and indane-5-carboxaldehyde(3.46 g, 23 mmol) was added aniline (2.20 g, 23 mmol, 1 eq). Theresultant solution slowly solidfied to a mixture of imines which wasrecrystallized from hot acetonitrile to yield the 5-aldimine as a whitesolid. The aldimine (2.65 g) was suspended in water (6 mL), and treatedwith 4 N hydrochloric dioxane (10 mL). The mixture was boiled for 1hour, cooled to room temperature, and poured into ether. The organicsolution was dried over MgSO₄, filtered, and concentated in vacuo.Vacuum distillation of the residue afforded indane-5-carboxaldehyde(1.54 g, 88%) as a colorless liquid. b.p. 88-90° C. at 0.9 mm Hg.

EXAMPLE 142Btrans,trans-1-(N-Methyl-N-propylaminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(5-indanyl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting indane-5-carboxaldehyde for piperonal in Example49A. ¹H NMR (300 MHz, CDCl₃) (minor rotamer) δ 7.25-7.1 (5H, m), 6.78(2H, d, J=8 Hz), 3.89 (1H, d, J=8 Hz), 3.75 (3H, s), 3.50-2.90 (6H, m),2.88 (6H, t, J=6 Hz), 2.82 (2.80) (3H, s), 2.04 (2H, t, J=8 Hz), 1.48(2H, septet, J=7 Hz), 0.83 (0.73) (3H, t, J=7 Hz). MS (DCl/NH₃) m/e 451(M+H)⁺, 473 (M+Na)⁺. Anal.calc. for C₂₇H₃₄N₂O₄.2.5 H₂O: C, 65.44; H,7.93; N, 5.65. Found: C, 65.36; H, 7.45; N, 5.53.

EXAMPLE 143trans,trans-1-(N-Methyl-N-propylaminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(6-indolyl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting indole-6-carboxaldehyde, prepared by the method ofRapoport, J. Org. Chem. 51: 5106 (1986), for piperonal in Example 49A.¹H NMR (300 MHz, CDCl₃) (minor rotamer) δ 8.43 (1H, brs), 7.57 (1H, d,J=8 Hz), 7.43 (1H, s), 7.31 (2H, dd, J=6 Hz, 3 Hz), 7.22 (1H, J=8 Hz),7.1 (1H, t, J=3 Hz), 6.78 (2H, dd, J=6 Hz, 3 Hz), 6.45 (1H, m), 3.93(1H, dd, J=6 Hz, 3 Hz), 3.80 (1H, m), 3.73 (3H, s), 3.60-2.90 (6H, m),2.86 (2.82) (3H, s), 1.47 (2H, septet, J=7 Hz), 0.83 (0.731 (3H, t, J=7Hz). MS (DCl/NH₃) m/e 450 (M+H)⁺. Anal.calc. for C₂₆H₃₁N₃O₄.0.75 H₂O: C,67.44; H, 7.07; N, 9.07. Found: C, 67.42; H, 7.09; N, 8.91.

EXAMPLE 144trans,trans-1-(N-Methyl-N-propylaminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(3,4-difluorophenyl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting 3,4-difluorobenzaldehyde for piperonal in Example49A. ¹H NMR (300 MHz, CDCl₃) (minor rotamer) δ 7.60-7.3 (4H, m), 7.13(1H, q, J=9 Hz), 6.90 (2H, d, J=8 Hz), 3.90 (1H, m), 3.79 (3H, s),3.60-2.95 (6H, m), 2.92 (2.78) (3H, s), 1.55 (2H, septet, J=7 Hz), 0.88(0.73) (3H, t, J=7 Hz). MS (DCl/NH₃) m/e 447 (M+H)⁺. Anal.calc. forC₂₄H₂₈F₂N₂O₄.1.80 H₂O: C, 60.19; H, 6.65; N, 5.85. Found: C, 60.13; H,6.34; N, 5.84.

EXAMPLE 145trans,trans-1-(N-Methyl-N-propylaminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(phenyl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting benzaldehyde for piperonal in Example 49A. ¹H NMR(300 MHz, CDCl₃) (minor rotamer) δ 7.53 (4H, d, J=6 Hz), 7.40-7.20 (3H,m), 6.88 (2H, d, J=8 Hz), 3.90 (1H, m), 3.79 (3H, s), 3.70-2.95 (8H, m),2.90 (2.79) (3H, s), 1.50 (2H, sept, J=7 Hz), 0.87 (0.72) (3H, t, J=7Hz). MS (DCl/NH₃) m/e 411 (M+H)⁺. Anal.calc. for C₂₄H₃₀N₂O₄.2.00 H₂O: C,64.55; H, 7.67; N, 6.27. Found: C, 64.37; H, 7.43; N, 6.29.

EXAMPLE 146trans,trans-1-(N-Methyl-N-propylaminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(4-hydroxyphenyl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting 4-hydroxybenzaldehyde for piperonal in Example49A. ¹H NMR (300 MHz, CDCl₃-CD₃OD) (minor rotamer) δ 7.35 (2H, d, J=8Hz), 7.28 (2H, dd, J=7 Hz, 3 Hz), 6.90 (2H, dd, J=7 Hz, 3 Hz), 6.89 (2H,d, J=8 Hz), 3.81 (3H, s), 3.65 (1H, d, J=8 Hz), 3.70-3.00 (8H, m), 2.92(2.83) (3H, s), 1.50 (2H, septet, J=7 Hz), 0.87 (0.77) (3H, t, J=7 Hz).MS (DCl/NH₃) m/e 427 (M+H)⁺. Anal.calc. for C₂₄H₃₀N₂O₅.1.00 H₂O: C,64.85; H, 7.26; N, 6.30. Found: C, 64.82; H, 7.39; N, 6.46.

EXAMPLE 147trans,trans-1-(N-Methyl-N-propylaminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(2,4-dimethoxyphenyl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49. substituting 2,4-dimethoxybenzaldehyde for piperonal inExample 49A. ¹H NMR (300 MHz, CDCl₃-CD₃OD) (minor rotamer) δ 7.61 (1H,d, J=8 Hz), 7.30 (2H, d, J=8 Hz), 6.82 (2H, d, J=8 Hz), 6.55 (1H, d, J=8Hz), 6.45 (1H, d, J=3 Hz), 3.90 (1H, m), 3.81 (3H, s), 3.79 (3H, s),3.77 (3H, s), 3.70-2.90 (8H, m), 2.85 (3H, s), 1.50 (2H, sept, J=7 Hz),0.87 (0.77) (3H, t, J=7 Hz). MS (DCl/NH3) m/e 471 (M+H)⁺. Anal.calc. forC₂₆H₃₄N₂O₆.0.75 H₂O: C, 64.51; H, 7.39; N, 5.79. Found: C, 64.65; H,7.07; N, 5.75.

EXAMPLE 148trans,trans-1-(N,N-Di(n-Butyl)aminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(5-benzo-2,3-dihydrofuranyl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting 2,3-dihydrobenzofuran-5-carboxaldehyde forpiperonal in Example 49A. ¹H NMR (300 MHz, CDCl₃) 8 7.31 (2H, d, J=8Hz), 7.27 (1H, d, J=2 Hz), 7.18 (1H, dd, J=7 Hz, 3 Hz), 6.86 (2H, d, J=8Hz), 6.72 (1H, d, J=8 Hz), 4.56 (2H, t, J=7 Hz), 3.78 (3H s), 3.62 (1H,m), 3.50-3.25 (4H, m), 3.17 (2H, t, J=7 Hz), 3.15-2.90 (5H, m), 2.79(1H, d, J=14 Hz), 1.43 (3H, m), 1.26 (3H, m), 1.08 (2H, m), 0.87 (3H, t,J=7 Hz), 0.81 (3H, t, J=7 Hz). MS (DCl/NH₃) m/e 509 (M+H)⁺. Anal.calc.for C₃₀H₄₀N₂O₅.0.25 H₂O: C, 70.22; H, 7.95; N, 5.46. Found: C, 70.21; H,7.92; N, 5.36.

EXAMPLE 149trans,trans-1-(N,N-Di(n-Butyl)aminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(4-methoxyphenyl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting 4-methoxybenzaldehyde for piperonal in Example49A. ¹H NMR (300 MHz, CDCl₃) δ 7.38 (2, d, J=8 Hz), 7.30 (2H, d, J=8Hz), 6.87 (4H, dd, J=7 Hz, 3 Hz), 3.78 (3H, s), 3.76 (3H, s), 3.63 (1H,m), 3.50-3.20 (4H, m), 3.15-2.90 (5H, m), 2.78 (1H, d, J=14 Hz), 1.43(3H, m), 1.27 (3H, m), 1.09 (2H, m), 0.87 (3H, t, J=7 Hz), 0.81 (3H, t,J=7 Hz). MS (DCl/NH₃) m/e 497 (M+H)⁺. Anal.calc. for C₂₉H₄₀N₂O₅: C,70.13; H, 8.12; N, 5.64. Found: C, 69.78; H, 8.10; N, 5.54.

EXAMPLE 150trans,trans-1-(N,N-Di(n-Butyl)aminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(3,4-difluorophenyl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting 3,4-difluorobenzaldehyde for piperonal in Example49A. ¹H NMR (300 MHz, CDCl₃) δ 7.35 (1H, m), 7.30 (2H, d, J=8 Hz),7.20-7.00 (2H, m), 6.87 (2H, d, J=8 Hz), 3.78 (3H, s), 3.79 (1H, m),3.62 (1H, m), 3.50-3.30 (3H, m), 3.23 (1H, m), 3.15-2.90 (4H, m), 2.78(1H, d, J=14 Hz), 1.43 (2H, m), 1.27 (4H, m), 1.08 (2H, m), 0.85 (3H, t,J=7 Hz), 0.80 (3H, t, J=7 Hz). MS (DCl/NH₃) m/e 503 (M+H)⁺. Anal.calc.for C₂₈H₃₆F₂N₂O₄.1 H₂O: C, 64.60; H, 7.36; N, 5.38. Found: C, 64.59; H7.20; N, 5.35.

EXAMPLE 151trans,trans-1-(N,N-Di(n-Butyl)aminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(2,4-dimethoxyphenyl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting 2,4-dimethoxybenzaldehyde for piperonal in Example49A. ¹H NMR (300 MHz, CDCl₃) δ 7.37 (2H, d, J=8 Hz), 7.20 (1H, d, J=8Hz), 6.92 (2H, d, J=8 Hz), 6.60 (1H, d, J=3 Hz), 6.49 (1H, dd, J=6 Hz, 2Hz), 5.35 (1H, d, J=8 Hz), 4.20 (3H, m), 4.10 (3H, s), 3.83 (3H, s),3.81 (3H, s), 3.75 (3H, m), 3.17 (2H, hep, J=7 Hz), 3.05 (2H, t, J=7Hz), 1.30 (4H, m), 1.07 (4H, m), 0.87 (3H, t, J=7 Hz), 0.80 (3H, t, J=7Hz). MS (DCl/NH₃) m/e 527 (M+H)⁺. Anal.calc. for C₃₀H₄₂N₂O₆.1.30 TFA: C,58.02; H, 6.47; N, 4.15. Found: C, 57.92; H, 6.43; N, 4.07.

EXAMPLE 152trans,trans-1-(N,N-Di(n-Butyl)aminocarbonylmethyl)-2-phenyl-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting ethyl benzoylacetate in Example 49B. ¹H NMR (300MHz, CDCl₃) δ 7.50-7.25 (5H, m), 7.04 (1H, d, J=3 Hz), 6.87 (1H, dd, J=7Hz, 3 Hz), 6.74 (1H, d, J=8 Hz), 5.94 (1H, d, J=4 Hz), 5.92 (1H, d, J=4Hz), 3.85 (1H, d, J=8 Hz), 3.64 (1H, m), 3.42 (3H, m), 3.27 (2H, m),3.20-2.90 (5H, m), 2.81 (1H, d, J=14 Hz), 1.43 (2H, m), 1.27 (4H, m),1.05 (2H, m), 0.85 (3H, t, J=7 Hz), 0.80 (3H, t, J=7 Hz). MS (DCl/NH₃)m/e 481 (M+H)⁺. Anal.calc. for C₂₈H₃₆N₂O₅: C, 69.98; H, 7.55; N, 5.83.Found: C, 69.69; H, 7.63; N, 5.71.

EXAMPLE 153trans,trans-1-(N,N-Di(n-Butyl)aminocarbonylmethyl)-2-phenyl-4-(5-benzo-2,3-dihydrofuranyl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting ethyl benzoylacetate in Example 49B and2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. ¹HNMR (300 MHz, CDCl₃) δ 7.53 (2H, m), 7.40 (4H, m), 7.13 (1H, dd, J=7 Hz,3 Hz), 6.72 (1H, d, J=8 Hz), 5.40 (1H, d, J=10 Hz), 4.56 (2H, t, J=8Hz), 4.18 (1H, d, J=14 Hz), 4.07 (2H, m), 3.79 (2H, m), 3.48 (1H, d,J=14 Hz), 3.35 (1H, m), 3.28 (3H, m), 2.95 (2H, m), 1.47 (2H, m), 1.28(4H, m), 1.10 (2H, m), 0.93 (3H, t, J=7 Hz), 0.78 (3H, t, J=7 Hz). MS(DCl/NH₃) m/e 479 (M+H)⁺. Anal.calc. for C₂₉H₃₈N₂O₄.1.10 TFA: C, 62.04;H, 6.52; N, 4.64. Found: C, 61.89; H, 6.44; N, 4.57.

EXAMPLE 154trans,trans-1-(N,N-Di(n-Butyl)aminocarbonylmethyl)-2-(4-t-butylphenyl)-4-(5-benzo-2,3-dihydrofuranyl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting t-butyl benzoylacetate, prepared by the method ofKrapcho et al., Org. Syn. 47:20 (1967) starting from4-t-butylacetophenone, in Example 49B and2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. ¹HNMR (300 MHz, CDCl₃) δ 7.60-7.30 (6H, m), 6.90 (1H, m), 4.50 (2H, m),3.95 (1H, m), 3.85-2.95 (11H, m), 2.90 (11H, d, J=14 Hz), 1.58 (2H, m),1.50 (7H, m), 1.41 (6H, (111H, m), 2.90 (11H, d, J=14 Hz), 1.58 (2H, m),1.50 (7H, m), 1.41 (6H, m/e 535 (M+H)⁺. Anal.calc. for C₃₃H₄₆N₂O₄.0.25H₂O: C, 73.50; H, 8.69; N, 5.19. Found: C, 73.57; H, 8.58; N, 5.14.

EXAMPLE 155trans,trans-2-(N,N-Di(n-Butyl)aminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(4-fluorophenyl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting 4-fluorobenzaldehyde for piperonal in Example 49A.¹H NMR (300 MHz, CDCl₃) δ 7.50 (1H, m), 7.42 (1H, dd, J=7 Hz, 3 Hz),7.36 (2H, d, J=8 Hz), 7.01 (3H, t, J=8 Hz), 6.87 (1H, d, J=8 Hz), 3.83(11H, m), 3.8 (3H, s), 3.67 (11H, m), 3.47 (3H, m), 3.30-2.90 (5H, m),2.82 (1H, d, J=14 Hz), 1.43 (2H, m), 1.28 (4H, m), 1.08 (2H, m), 0.90(3H, t, J=7 Hz), 0.82 (3H, t, J=7 Hz). MS (DCl/NH₃) m/e 485 (M+H)⁺.Anal.calc. for C₂₈H3₇FN₂O₄: C, 69.40; H, 7.70; N, 5.78. Found: C, 69.03;H, 8.00; N, 5.74.

EXAMPLE 156trans,trans-1-(N,N-Di(n-Butyl)aminocarbonylmethyl)-2-(3-furyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting β-oxo-3-furanpropionate in Example 49B. ¹H NMR(300 MHz, CDCl₃) δ 7.41 (2H, m), 6.97 (1H, d, J=3 Hz), 6.85 (1H, dd, J=7Hz, 3 Hz), 6.72 (1H, d, J=8 Hz), 6.42 (11H, s), 5.94 (11H, d, J=4 Hz),5.92 (1H, d, J=4 Hz), 3.90 (1H, m), 3.70-3.25 (5H, m), 3.20-2.90 (4H,m), 2.85 (1H, d, J=14 Hz), 1.43 (2H, m), 1.40-1.05 (6H, m), 0.90 (6H,m). MS (DCl/NH₃) m/e 471 (M+H)⁺. Anal.calc. for C₂₆H₃₄N₂O₆: C, 66.36; H,7.28; N, 5.95. Found: C, 66.09; H, 7.24; N, 5.87.

EXAMPLE 157trans,trans-1-(N,N-Di(n-Butyl)aminocarbonylmethyl)-2-(isopropyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting ethyl isobutyrylacetate in Example 49B. ¹H NMR(300 MHz, CDCl₃) δ 6.85 (1H, d, J=2 Hz), 6.76 (1H, dd, J=6 Hz, 2 Hz),6.71 (1H, d, J=8 Hz), 5.92 (2H, s), 3.75 (1H, d, J=14 Hz), 3.66 (1H, q,J=7 Hz), 3.42 (3H, m), 3.25 (3H, m), 3.11 (2H, m), 2.83 (1H, t, J=7 Hz),1.88 (1H, m), 1.55 (4H, m), 1.32 (4H, m), 0.92 (12H, m). MS (DCl/NH₃)m/e 447 (M+H)⁺. Anal.calc. for C₂₅H₃₈N₂O₅.0.50 H₂O: C, 65.91; H, 8.63;N, 6.15. Found: C, 66.07; H, 8.10; N, 6.03.

EXAMPLE 158trans,trans-1-(N,N-Di(n-Butyl)aminocarbonylmethyl)-2-(4-t-butylphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 -substituting ethyl 4-t-butylbenzoylacetate, prepared by themethod of Krapcho et al., Org. Syn. 47: 20. (1967) starting with4-t-butylacetophenone), in Example 49B. ¹H NMR (300 MHz, CDCl₃) δ 7.32(4H, d, J=3 Hz), 7.04 (1H, d, J=2 Hz), 6.87 (1H, dd, J=8 Hz, 3 Hz), 6.74(1H, d, J=9 Hz), 5.94 (1H, d, J=4 Hz), 5.92 (1H, d, J=4 Hz), 3.77 (1H,d, J=14 Hz), 3.65-3.25 (5H, m), 3.15-2.85 (4H, m), 2.73 (1H, d, J=14Hz), 1.45 (2H, m), 1.29 (13H, s), 1.00 (2H, m), 0.86 (3H, t, J=7 Hz),0.76 (3H, t, J=7 Hz). MS (DCl/NH₃) m/e 537 (M+H)⁺. Anal.calc. forC₃₂H₄₄N₂O₅: C, 71.61; H, 8.26; N, 5.22. Found: C, 71.43; H, 8.09; N,5.11.

EXAMPLE 159trans,trans-1-(N,N-Di(n-Butyl)aminocarbonylmethyl)-2-(4-t-butylphenyl)-4-(5-benzo-2,3-dihydrofuranyl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting ethyl isobutyrylacetate in Example 49B and2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. ¹HNMR (300 MHz, CDCl₃) δ 7.30 (1H, s), 7.13 (1H, dd, J=7 Hz, 2 Hz), 6.82(1H, d, J=8 Hz), 4.68 (2H, t, J=8 Hz), 4.48 (1H, s), 3.19 (3H, m), (3H,m), 3.48 (2H, m), 3.3 (5H, m), 2.41 (1H, m), 1.65 (4H, m), 1.44 (4H, m),1.21 (3H, d, J=5 Hz), 1.17 (3H, d, J=5 Hz), 1.05 (6H, m). MS (DCl/NH₃)m/e 445 (M+H)⁺. Anal.calc. for C₂₆H₄₀N₂O₄.1.2 TFA: C, 58.67; H, 7.14; N,4.8.2 Found: C, 58.54; H, 7.25; N, 4.74.

EXAMPLE 160trans,trans-1-(N,N-Di(n-Butyl)aminocarbonylmethyl)-2-(anti-4-methoxycyclohexyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid EXAMPLE 160A syn and anti Ethyl 4-Methoxycyclohexanoylacetate

Syn, anti-4-Methoxycyclohexane carboxylic acid (5.00 g, 31.6 mmol) andcarbonyldiimidazole (6.15 g, 37.9 mmol, 1.2 eq) were stirred inanhydrous tetrahydrofuran (50 mL) for 6 hours at room temperature. Atthe same time, magnesium chloride (3.01 g, 31.6 mmol) and ethyl malonatepotassium salt (7.52 g, 44.2 mmol, 1.4 equivalents) were stirred inanhydrous tetrahydrofuran (75 mL) for 6 hours at 50° C. The mixture wascooled to room. temperature, and the imidazole-acid mixture added to it.The reaction stirred overnight at room temperature. The solvents wereremoved under reduced pressure, and the residue was taken up inchloroform/water. The organic phase washed with 5% potassium bisultate,water, and brine, dried with magnesium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by flashchromatography on 175 g silica gel, eluting with 20% ethyl acetate inhexanes. Pure fractions of the syn and anti methoxycyclohexyl β-ketoesters were obtained. The solvents were removed under reduced pressureto yield the trans-4-methoxycyclohexyl β-keto ester (914 mg) as acolorless oil and the cis 4-methoxycyclohexyl β keto ester (1.07 g) as acolorless oil.

EXAMPLE 160Btrans,trans-1-(N,N-Di(n-Butylaminocarbonylmethyl)-2-(anti-4-methoxycyclohexyl)-4-1,3-beanzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting the anti-compound resulting from Example 160A inExample 49B. ¹H NMR (300 MHz, CDCl₃) δ 6.84 (1H, d, J=2 Hz), 6.76 (1H,dd, J=7 Hz, 2 Hz), 6.61 (1H, d, J=8 Hz), 5.92 (2H, s), 3.69 (2H, m),3.50-3.27 (5H, m), 3.26 (3H, s), 3.25-3.00 (3H, m), 2.88 (1H, m), 1.95(2H, m), 1.62 (7H, m), 1.33 (9H, m), 0.97 (3H, t, J=7 Hz), 0.92 (3H, tJ=7 Hz). MS. (DCl/NH₃) m/e 517 (M+H)⁺. Anal.calc. for C₂₉H₄₄N₂O₆.0.50H₂O: C, 66.26; H, 8.63; N, 5.33. Found: C, 66.27; H, 8.50; N, 5.13.

EXAMPLE 161trans,trans-1-(N,N-Di(n-Butyl)aminocarbonylmethyl)-2-(syn-4-methoxycyclohexyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting the syn-compound resulting from Example 160A inExample 49B. ¹H NMR (300 MHz, CDCl₃) δ 6.84 (1H, d, J=2 Hz), 6.77 (1H,dd, J=6 Hz, 2 Hz), 6.61 (1H, d, J=8 Hz), 5.92 (2H, s), 3.65 (2H, m),3.42 (2H, m), 3.32 (3H, s), 3.30-3.00 (6H, m), 2.82 (1H, m), 2.10 (2H,m), 1.83 (2H, m), 1.52 (6H, m), 1.33 (4H, m), 1.20-1.00 (4H, m), 0.96(3H, t, J=7 Hz), 0.91 (3H, t, J=7 Hz). MS (DCl/NH₃) m/e 517 (M+H)⁺.Anal.calc. for C₂₉H₄₄N₂O₆.0.30 H₂O: C, 66.72; H, 8.61; N, 5.37. Found:C, 66.76; H, 8.65; N, 5.28.

EXAMPLE 162trans,trans-1-(N,N-Di(n-Butyl)aminocarbonylmethyl)-2,4-di(5-benzo-2,3-dihydrofuranyl)pyrrolidine-3-carboxylicAcid EXAMPLE 162A 5-Acetyl-2,3-dihydrobenzofuran

To a 0° C. solution of acetyl chloride (1.64 mL, 23.0 mmol, 1.3equivalents) in methylene chloride (30 mL) was added stannic chloride(2.49 mL, 21.3 mmol, 1.2 equivalents), maintaining the temperature below5° C. The solution was stirred 15 minutes at 0° C., and then a solutionof 2,3-dihydrofuran (2.00 mL, 17.7 mmol) in methylene chloride (5 mL)was added dropwise while maintaining the temperature below 8° C. Thedark red solution was stirred 1 hour at 2° C. and then poured into 50 mLof ice water. The reaction was stirred an additional 30 minutes, and thelayers were separated. The organic layer was washed with water andaqueous sodium bicarbonate, dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by flashchromatography on 150 g silica gel, eluting with 18% ethyl acetate inhexanes. The solvents were removed under reduced pressure to yield thetitle compound (2.68 g, 93%) as a yellow solid.

EXAMPLE 162Btrans,trans-1-(N,N-Di(n-Butyl)aminocarbonylmethyl)-2,4-di(5-benzo-2,3-dihydrofuranyl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting the compound resulting from Example 162A inExample 49B and 2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal inExample 49A. ¹H NMR (300 MHz, CDCl₃) δ 7.43 (1H, s), 7.38 (1H, s), 7.06(2H, m), 6.75 (1H, d, J=6 Hz), 6.70 (1H, d, J=6 Hz), 5.40 (1H, d, J=9Hz), 4.58 (4H, q, J=7 Hz), 4.16 (1H, d, J=14 Hz), 4.09 (2H, m), 3.82(2H, m), 3.57 (1H, d, J=14 Hz), 3.38 (1H, m), 3.30-3.05 (6H, m), 2.95(2H, q, J=6 Hz), 1.50 (2H, m), 1.30 (4H, m), 1.15 (2H, m), 0.94 (3H, t,J=7 Hz), 0.83 (3H, t, J=7 Hz). MS (DCl/NH₃) m/e 521 (M+H)⁺. Anal.calc.for C₃₁H₄₀N₂O₅.1.25 TFA: C, 60.67; H, 6.27; N, 4.22. Found: C, 60.49; H,6.18; N, 4.13.

EXAMPLE 163trans,trans-1-(N,N-Di(n-Butyl)aminocarbonylmethyl)-2-(3-furyl)-4-(5-benzo-2,3-dihydrofuranyl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting ethyl β-oxo-3-furanpropionate in Example 49B and2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. ¹HNMR (300 MHz, CDCl₃) δ 7.42 (1H, m), 7.38 (1H, m), 7.13 (1H, s), 7.16(1H, dd, J=7 Hz, 3 Hz), 6.70 (1H, d, J=8 Hz), 6.41 (1H, m), 4.57 (2H, t,J=7 Hz), 3.95 (1H, d, J=8 Hz), 3.63 (1H, m), 3.55 (1H, d, J=14),3.50-3.25 (4H, m), 3.18 (2H, t, J=6 Hz), 3.15-2.95 (3H, m), 2.87 (1H, d,J=14 Hz), 1.45 (4H, m), 1.35-1.10 (4H, m), 0.85 (6H, m). MS (DCl/NH₃)m/e 469 (M+H)⁺. Anal.calc. for C₂₇H₃₆N₂O₅.0.25 H₂O: C, 68.55; H, 7.78;N, 5.92. Found: C, 68.62; H, 7.68; N, 5.82.

EXAMPLE 164trans,trans-1-(N,N-Di(n-Butyl)aminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(3-fluorophenyl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting 3-fluorobenzenecarboxaldehyde for piperonal inExample 49A. ¹H NMR (300 MHz, CDCl₃) δ 7.30 (2H, d, J=8 Hz), 7.22 (2H,m), 6.91 (1H, m), 6.86 (2H, d, J=8 Hz), 3.79 (1H, m), 3.78 (3H, s), 3.68(1H, m), 3.55-3.37 (3H, m), 3.29 (1H, m), 3.15-2.90 (5H, m), 2.78 (1H,d, J=14 Hz), 1.43 (2H, m), 1.25 (4H, m), 1.07 (2H, m), 0.87 (3H, t, J=7Hz), 0.80 (3H, t, J=7 Hz). MS (DCl/NH₃) m/e 485 (M+H)⁺. Anal.calc. forC₂₈H₃₇FN₂O₄.0.25 H₂O: C, 68.76; H, 7.73; N, 5.73. Found: C, 68.87; H,7.69; N, 5.67.

EXAMPLE 165trans,trans-1-(N,N-Di(n-Butyl)aminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(3-pyridyl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting 3-pyridinecarboxaldehyde for piperonal in Example49A. The nitro styrene was prepared by the method of Bourguignon, etal., Can. J. Chem. 63: 2354 (1985). ¹H NMR (300 MHz, CDCl₃) δ 8.82 (1H,bs), 8.73 (1H, bd, J=9 Hz), 8.62 (1H, bd, J=7 Hz), 7.78 (1H, bdd, J=9Hz, 3 Hz), 7.38 (2H, d, J=10 Hz), 6.90 (2H, d, J=10 Hz), 4.39 (1H, d,J=12 Hz), 3.95 (1H, m), 3.80 (3H, s), 3.79 (1H, m), 3.68 (1H, d, J=18Hz), 3.50-3.30 (3H, m), 3.25-2.90 (6H, m), 1.47 (2H, m), 1.31 (4H, m),1.20 (2H, m), 0.92 (3H, t, J=7 Hz), 0.83 (3H, t, J=7 Hz). MS (DCl/NH₃)m/e 468 (M+H)⁺. Anal.calc. for C₂₇H₃₇N₃O₄.1.65 TFA: C, 55.50; H, 5.94;N, 6.41. Found: C, 55.53; H, 5.90; N, 6.27.

EXAMPLE 166trans,trans-1-(N,N-Di(n-Butyl)aminocarbonylmethyl)-2-(2-fluorophenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting ethyl 2-fluorobenzoylacetate in Example 49B. ¹HNMR (300 MHz, CDCl₃) δ 7.52 (1H, dt, J=7 Hz, 3 Hz), 7.25 (1H, m), 7.13(1H, dt, J=7 Hz, 3 Hz), 7.02 (2H, m), 6.88 (1H, dd, J=7 Hz, 3 Hz), 6.73(1H, d, J=8 Hz), 5.93 (1H, d, J=4 Hz), 5.92 (1H, d, J=4 Hz), 4.25 (1H,d, J=9 Hz), 3.68 (1H, m), 3.42 (3H, m), 3.39 (1H, m), 3.20-2.95 (4H, m),2.91 (1H, d, J=14 Hz), 1.45 (3H, m), 1.26 (3H, m), 1.08 (2H, m), 0.87(3H, t, J-7 Hz), 0.81 (3H, t, J=7 Hz). MS (DCl/NH₃) m/e 499 (M+H)⁺.Anal.calc. for C₂₈H₃₅FN₂O₅.0.25 H₂O: C, 66.85; H, 7.11; N, 5.57. Found:C, 66.51; H, 6.67; N, 5.18.

EXAMPLE 167trans,trans-1-(N,N-Di(n-Butyl)aminocarbonylmethyl)-2-(3-fluorophenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

The title compound was prepared by the procedures described in Examples1 and 49 substituting ethyl 3-fluorobenzoylacetate in Example 49B. ¹HNMR (300 MHz, CDCl₃) δ 7.38 (1H, m), 7.18 (1H, d, J=7 Hz), 7.15 (1H, m),7.00 (1H, d, J=2 Hz), 6.95 (1H, m), 6.86 (1H, dd, J=7 Hz, 2 Hz), 6.75(1H, d, J=8 Hz), 5.93 (1H, d, J=4 Hz), 5.92 (1H, d, J=4 Hz), 3.94 (1H,d, J=14 Hz), 3.63 (1H, m), 3.42 (3H, m), 3.35-2.95 (5H, m), 2.87 (1H, d,J=14 Hz), 1.44 (3H, m), 1.27 (3H, m), 1.10 (2H, m), 0.88 (3H, t, J=7Hz), 0.81 (3H, t, J=7 Hz). MS (DCl/NH₃) m/e 499 (M+H)⁺. Anal.calc. forC₂₈H₃₅FN₂O₅: C, 67.45; H, 7.08; N, 5.62. Found: C, 67.32; H, 7.05; N,5.40.

EXAMPLE 168trans,trans-1-(4-N,N-Di((n-Butyl)aminophenyl)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

4-Nitro-1-fluorobenzene, ethyltrans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate(the compound resulting from Example 6A), and diisopropylethylamine areheated in dioxane to give ethyltrans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(4-nitrophenyl)-pyrrolidine-3-carboxylate.

The nitro compound is hydrogenated to give the corresponding aminophenylcompound. The aminophenyl compound is reacted with butyraldehyde andsodium cyanoborohydride according to the method of Borch, J. Am Chem,Soc. 93: 2897 (1971) to give the corresponding N,N-dibutylaminophenylcompound. Hydrolysis with sodium hydroxide using the method of Example1D affords the title compound.

EXAMPLE 169trans,trans-1-(2-N,N-Dibutylaminopyrimidin-4-yl)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylicAcid

2-(Dibutylamino)-4-chloropyrimidine is prepared from2,4-dichloropyrimidine according to the method of Gershon, J.Heterocyclic Chem. 24: 205 (1987) and reacted with ethyltrans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate(the compound resulting from Example 6A) and diisoproplyethylamine indioxane with heating to give the intermediate ethyl ester, which ishydrolyzed with sodium hydroxide using the method of Example 1D to thetitle compound.

EXAMPLES 170-266

Using the procedures described in Examples 1, 4, 5, 7, 8 and 9 andScheme X, the following compounds can be prepared.

Ex. No. Name

170trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(isopropylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

171trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(ethylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

172trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(1-methylpropylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

173trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

174trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(piperidinylcarbonylmethyl)-pyrrolidine-3-carboxylicacid;

175trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(1-(propylaminocarbonyl)ethyl)-pyrrolidine-3-carboxylicacid;

176trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(α-(propylaminocarbonyl)benzyl)-pyrrolidine-3-carboxylicacid;

177trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(bis-(propylaminocarbonyl)methyl)-pyrrolidine-3-carboxylicacid;

178trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(propylaminocarbonyl)ethyl)-pyrrolidine-3-carboxylicacid;

179trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(propylaminosulfonylmethyl)-pyrrolidine-3-carboxylicacid;

180trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-phenethyl)-pyrrolidine-3-carboxylicacid;

181trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(pentanoylmethyl)-pyrrolidine-3-carboxylicacid;

182trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(benzoylmethyl)-pyrrolidine-3-carboxylicacid;

183trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(hexyl)-pyrrolidine-3-carboxylicacid;

184trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-hexynyl)-pyrrolidine-3-carboxylicacid;

185trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(propoxymethylcarbonylpyrrolidine-3-carboxylicacid;

186trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(phenylacetyl)-pyrrolidine-3-carboxylicacid;

187trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(anilinylcarbonyl)-pyrrolidine-3-carboxylicacid;

188trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-acetylaminoethyl)-pyrrolidine-3-carboxylicacid;

189trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-phenoxyethyl)-pyrrolidine-3-carboxylicacid;

190trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-benzodioxanylmethyl)-pyrrolidine-3-carboxylicacid;

191trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-tetrahydrofuranylmethyl)-pyrrolidine-3-carboxylicacid;

192trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(propylaminocarbonylamino)ethenyl)-pyrrolidine-3-carboxylicacid;

193trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(propylaminocarbonylamino)ethyl)-pyrrolidine-3-carboxylicacid;

194trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(3-oxohex-1-enyl)-pyrrolidine-3-carboxylicacid;

195trans,trans-2-(2,4-Dimethoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(propylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

196trans,trans-2-(2-Carboxy-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(propylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

197trans,trans-2-(2-Aminocarbonyl-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(propylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

198trans,trans-2-(2-Methanesulfonamido-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(propylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

199trans,trans-2-(2-Aminocarbonylmethoxy-4-methoxyphenyl)-4-(1,3-benzodioxol-5yl)-1-(propylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

200trans,trans-2-(2-Methoxyethoxy-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(propylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

201trans,trans-2-(2-Carboxymethoxy-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(propylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

202trans,trans-2-(4-Methoxy-2-tetrazolylmethoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(propylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

203trans,trans-2-(2-Allyloxy-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(propylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

204 trans,trans2,4-Bis(4-methoxyphenyl)-1-(propylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

205 trans,trans2,4-Bis(1,3-benzodioxol-5-yl)-1-(propylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

206trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-propylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

207trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxole-5-yl)-1-(N-methyl-N-butylaminocarbonyl)-pyrrolidine-3-carboxylicacid;

208trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-(4-methoxyphenyl)aminocarbonyl)-3-pyrrolidine-3-carboxylicacid;

209trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-phenylaminocarbonyl)-pyrrolidine-3-carboxylicacid;

210trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-allylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

211trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

212trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-isobutylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

213trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-cyclopentylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

214trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-(2-methoxyethyl)aminocarbonyl)-pyrrolidine-3-carboxylicacid;

215trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-butoxyethylaminocarbonyl)-pyrrolidine-3-carboxylicacid;

216trans,trans-2-(1,3-Benzodioxol-5-yl)-4-(4-methoxyphenyl)-1-(N-methyl-N-propylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

217trans,trans-2-(4-Methoxyphenyl)-4-(1,4-benzodioxan-6-yl)-1-(N-methyl-N-propylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

218trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-isopropylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

219trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-ethylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

220trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-(1-methylpropyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

221trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

222trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(1-(N-methyl-N-propylaminocarbonyl)ethyl)-pyrrolidine-3-carboxylicacid;

223trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(α-(N-methyl-N-propylaminocarbonyl)benzyl)-pyrrolidine-3-carboxylicacid;

224trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-ethyl-N-propylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

225trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxole-5-yl)-1-(N-ethyl-N-butylaminocarbonyl)-pyrrolidine-3-carboxylicacid;

226trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-ethyl-N-(4-methoxyphenyl)aminocarbonyl)-3-pyrrolidine-3-carboxylicacid;

227trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-ethyl-N-phenylaminocarbonyl)-pyrrolidine-3-carboxylicacid;

228trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-ethyl-N-allylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

229trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-ethyl-N-isobutylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

230trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-ethyl-N-cyclopentylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

231trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-ethyl-N-methoxyethylaminocarbonyl)-pyrrolidine-3-carboxylicacid;

232trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-ethyl-N-butoxyethylaminocarbonyl)-pyrrolidine-3-carboxylicacid;

233trans,trans-2-(1,3-Benzodioxol-5-yl)-4-(4-methoxyphenyl)-1-(N-ethyl-N-propylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

234trans,trans-2-(4-Methoxyphenyl)-4-(1,4-benzodioxan-6-yl)-1-(N-ethyl-N-propylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

235trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-ethyl-N-isopropylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

236trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-diethylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

237trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-ethyl-N-(1-methylpropyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;

238trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-ethyl-N-phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

239trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(1-(N-ethyl-N-propylaminocarbonyl)ethyl)-pyrrolidine-3-carboxylicacid;

240trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(α-(N-ethyl-N-propylaminocarbonyl)benzyl)-pyrrolidine-3-carboxylicacid;

241trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-isobutylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

242trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-cyclohexylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

243trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-dipropylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

244trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(isobutyloxyethyl)-pyrrolidine-3-carboxylicacid;

245trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(butylsulfonyl)-pyrrolidine-3-carboxylicacid;

246trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(isopropylsulfonylaminoethyl)-pyrrolidine-3-carboxylicacid;

247trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(ethoxymethylcarbonylmethyl)-pyrrolidine-3-carboxylicacid;

248trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-ethylbutyrylmethyl)-pyrrolidine-3-carboxylicacid;

249trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-(3,4-dimethoxybenzyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

250trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[(1R)-1-(N-methyl-N-propylaminocarbonyl)butyl]-pyrrolidine-3-carboxylicacid;

251trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[(1S)-1-(N-methyl-N-propylaminocarbonyl)butyl]-pyrrolidine-3-carboxylicacid;

252trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(3-isopropoxypropyl)-pyrrolidine-3-carboxylicacid;

253trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(5-methylhexyl)-pyrrolidine-3-carboxylicacid;

254trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(5-methyl-2-hexenyl)-pyrrolidine-3-carboxylicacid;

255 trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(5-methyl-4-hexenyl)-pyrrolidine-3-carboxylicacid;

256trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(3,5-dimethyl-2-hexenyl)-pyrrolidine-3-carboxylicacid;

257trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-methyl-N-isobutyrylamino)ethyl)-pyrrolidine-3-carboxylicacid;

258trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-(2,2-dimethylpropyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

259trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-ethyl-N-butylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

260trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-benzylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

262trans,trans-2-(4-Methoxyphenyl)-4-(5-indanyl)-1-(N-methyl-N-propylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

262trans,trans-2-(4-Methoxyphenyl)-4-(2,3-dihydrobenzofuran-5-yl)-1-(N-methyl-N-propylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

263trans,trans-2-(4-Methoxyphenyl)-4-(1-methylindol-5-yl)-1-(N-methyl-N-propylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

264trans,trans-2-(4-Methoxyphenyl)-4-(2-naphthyl)-1-(N-methyl-N-propylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

265trans,trans-2-(4-Methoxyphenyl)-4-(1,2-dimethoxy-4-phenyl)-1-(N-methyl-N-propylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

266trans,trans-2-(4-Methoxyphenyl)-4-(1-methoxy-3-phenyl)-1-(N-methyl-N-propylaminocarbonylmethyl)-pyrrolidine-3-carboxylicacid;

EXAMPLES 267-288

Following the procedures described in Example 1 and Scheme II, thefollowing compounds can be prepared.

267trans,trans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(propylaminocarbonylmethyl)-piperidine-4-carboxylicacid;

268trans,trans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(aminocarbonylmethyl)-piperidine-4-carboxylicacid;

269trans,trans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(4-fluorobenzyl)-piperidine-4-carboxylicacid;

270trans,trans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(2-ethoxyethyl)-piperidine-4-carboxylicacid;

271trans,trans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(2-propoxyethyl)-piperidine-4-carboxylicacid;

272trans,trans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-[2-(2-methoxyethoxy)ethyl]-piperidine-4-carboxylicacid;

273trans,trans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-[2-(2-pyridyl)ethyl]-piperidine-4-carboxylicacid;

274trans,trans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(morpholin-4-ylcarbonyl)-piperidine-4-carboxylicacid;

275trans,trans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxole-5-yl)-1-(butylaminocarbonyl)-piperidine-4-carboxylicacid;

276trans,trans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(4-methoxyphenylaminocarbonyl)-3-piperidine-4-carboxylicacid;

277trans,trans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-acetylpiperidine-3-carboxylicacid;

278trans,trans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(2-furoyl)-piperidine-3-carboxylicacid;

279trans,trans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(phenylaminocarbonyl)-piperidine-4-carboxylicacid;

280trans,trans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(allylaminocarbonylmethyl)-piperidine-4-carboxylicacid;

281trans,trans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(n-butylaminocarbonylmethyl)-piperidine-4-carboxylicacid;

282trans,trans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(N-n-butyl-N-methylaminocarbonylmethyl)-piperidine-4-carboxylicacid;

283trans,trans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(pyrrolidin-1-ylcarbonylmethyl)-piperidine-4-carboxylicacid;

284trans,trans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(isobutylaminocarbonylmethyl)-piperidine-4-carboxylicacid;

285trans,trans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(cyclopentylaminocarbonylmethyl)-piperidine-4-carboxylicacid;

286trans,trans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(morpholin-4-ylaminocarbonylmethyl)-piperidine-4-carboxylicacid;

287trans,trans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(2-phenoxyethyl)-piperidine-4-carboxylicacid;

288trans,trans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(methoxyethylaminocarbonyl)-piperidine-4-carboxylicacid.

EXAMPLE 289 trans,trans2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(4-dibutylaminophenyl)-pyrrolidine-3-carboxylicAcid

4-Nitro-fluorobenzene, ethyltrans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate(example 6A) and diisopropyl ethylamine are heated in dioxane to giveethyltrans,trans-2-(4-methoxyphoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(4-nitrophenyl)-pyrrolidine-3-carboxylate.The nitro compound is hydrogenated to the corresponding aminophenylcompound. This is reacted with butyraldehyde and sodium cyanoborohydrideaccording to the method of Borch (J. Am Chem. Soc., 93, 2897, 1971) togive the corresponding N,N-dibutylaminophenyl compound, which ishydrolyzed with sodium hydroxide using the method of example 1D to givethe title compound.

EXAMPLE 290trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-dibutylamino-pyrimidine-4-yl)-pyrrolidine-3-carboxylicAcid

2-(Dibutylamino) 4-chloropyrimidine is prepared from2-4-dichloropyrimidine according to the method of Gershon (J.Heterocyclic Chem. 24, 205, 1987). This compound, ethyltrans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate(example 6A), and di-isopropyl ethylamine are heated in dioxane to givethe intermediate ethyl ester, which is hydrolyzed with sodium hydroxideusing the method of example 1D to give the title compound.

EXAMPLE 291trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-butyl-N-phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

The title compound was prepared according to the general procedure ofExample 1. ¹H NMR (CD₃OD): δ 0.87 (t, 3H, J=8); 1.2-1.35 (m, 2H);1.35-1.5 (m, 2H); 2.78 (m, 2H); 3.10 (t, 1H, J=9); 3.26 (d, 1H, J=15);3.44 (dd, 1H, J=5, 10); 3.5-3.7 (m, 3H); 3.77 (m, 1H); 3.78 (s, 3H);5.93 (s, 2H); 6.7-6.9 (m, 4H); 7.0-7.2 (m, 5H); 7.4 (m, 3H). MS(DCl/NH₃): m/e 531 (M+H)⁺. Anal calcd for C₃₁H₃₄N₂O₆: C, 70.17; H, 6.46;N, 5.28. Found: C,70.36; H, 6.52; N, 4.99.

EXAMPLE 292 Sodiumtrans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-Butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylateEXAMPLE 292A Ethyl 3-(4-Methoxyphenyl)-3-oxopropionate

Simultaneous reactions were run in both a 65-L reactor and a 35-Lreactor that share the same reflux system. A nitrogen atmosphere wasmaintained in both. 4.0 kg (100 moles) of 60% sodium hydride in mineraloil and 32 L toluene were charged into the ambient temperature reactors.The mixture was agitated for 5 minutes and allowed to settle. 20 L ofthe toluene solution was aspirated. 28 L of toluene was added, agitatedfor 5 minutes, allowed to settle and 28 L of the toluene solution wasaspirated. 68 L of toluene and 8.4 L (69.7 moles) diethyl carbonate wereadded. The agitation was begun and the flow of Syltherm (Note 4) inreactor jackets was initiated. A solution of 5.0 kg (33.3 moles)4-methoxyacetophenone in 12 L toluene was added over 20 minutes. Whenadditions were complete, the jacket temperature was reduced to 10° C.and stirring continued for 16 hours. A solution of 6.7 L (117 moles)glacial acetic acid in 23 L deionized water was fed at the same ratethat was previously used for the acetophenone solution. When additionwas complete, agitation was stopped and the layers separated. Theaqueous layer was washed once with 13 L toluene. The combined organiclayers were washed twice with 6.7 L portions of 7% (w:w) aqueous sodiumbicarbonate. The toluene solution was washed once with 6.7 L of 23%(w:w) aqueous sodium chloride . The organic solution was dried over 10kg sodium sulfate, filtered, and the solvent removed on the rotaryevaporator to provide the desired product.

EXAMPLE 292B 3,4-Methylenedioxy-1-(2-nitroethenyl-benzene

In a 45-L cryogenic reactor with a contoured, anchor stirrer wasdissolved 5.537 kg (36.9 moles) piperonal in 9 L methanol and 2.252 kg(36.9 moles) nitromethane at 15°-20° C. The jacket temperature was setto −5° C. and the reaction solution cooled to a temperature of +3.5° C.A 21° C. solution of 3.10 kg (38.8 moles) 50% (w:w) aquous sodiumhydroxide diluted with 3.7 L water was pumped in. The reactiontemperature was maintained between 10°-15° C. When addition wascomplete, the jacket temperature was reset to 1° C. and stirringcontinued for 30 minutes. A mixture of 7 kg ice in 19 L water was addedto dissolve most of the solid. The reaction mixture was filtered throughcanvas and then a 27R10SV Honeycomb filter. The filtered solution wasmetered into a 21° C. mixture of 7.4 L concentrated hydrochloric acid in11.1 L deionized water. The final reaction temperature was 26° C. Theresulting product was centrifuged and washed until the wash pH rose toat least 6 (by pH indicating paper). The crude product was dissolved in92 L dichloromethane and the layers separated. The aqueous layer waswashed once with 8 L dichloromethane. The combined organics were driedover 1.32 kg magnesium sulfate and filtered through Whatman #1 paper.The volume was reduced to 20% and the solution cooled to 4° C.Filtration through Whatman #1 paper, followed by ambient temperaturedrying in vacuo with an air leak afforded 1.584 kg (22%) of a first cropConcentration of the MLS to 25% followed by similar cooling, filtration,and drying afforded 0.262 kg (4%) of a second crop. The yellow productdarkened on standing in light and air.

EXAMPLE 292C Ethyl2-(4-Methoxybenzoyl)-3-(1,3-benzodioxol-5-yl)-4-nitrobutanoate

Into a 45-L stirred reactor at ambient temperature were charged 5.819 kg(30.1 moles) 3,4-methylenedioxy-1-(2-nitroethenyl)-benzene and 24 Lethyl acetate . A solution of 5.355 kg (24.1 moles) ethyl3-(4-methoxyphenyl)-3-oxopropionate in 16 L ethyl acetate was added. 280g (275 ml, 1.84 moles) of 1,8-diaza-bicyclo[5.4.0]undec-7-ene in fourequal portions was added over a 2.5 hour period. The reaction mixturewas filtered through dicalite and the resulting filtered solution wasused in the next step without any further purification.

EXAMPLE 292D Ethyl2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-4,5-dihydro-3H-pyrrol-3-carboxylate

The product of Example 292C (1316 ml solution consisting of 300 g Ethyl2-(4-methoxybenzoyl)-3-(3,4-methylenedioxyphenyl)-4 nitrobutanoate inethyl acetate) was added to a glass reactor containing RaNi #28 (300 g).The reaction mixture was shaken under a hydrogen environment of 4 atm atroom temperature for 18 hours and filtered through a nylon 0.20 micron47 mm millipore.

The filtrate was concentrated to 1.4 kg of dark solution and purified bynormal phase silica gel chromatography eluting with 85:15, hexanes:ethylacetate. The pure fractions were combined and concentrated (as above)until crystals formed. The solution was cooled to 0° C. and filtered.The solid was washed with 2 L of 85:15, hexane: ethyl acetate (0° C.).The solids were dried in vacuo at 50° C. to a constant weight of 193.4 g(21% yield, melting point 80-81° C.) of the title compound. A further200 g (23% yield) of product was obtained from the mother liquors.

EXAMPLE 292E Ethyl2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine 3-carboxylate

Into a 12-L flask equipped with magnetic stirring, addition funnel,temperature probe, and nitrogen inlet was charged 0.460 kg ethyl2-(4-methoxyphenyl)-4-(3,4-methylenedioxyphenyl)-4,5-dihydro-3H-pyrrole-3-carboxylate(1.25 mol). The reaction vessel was degassed with nitrogen. Absolute 3.7L ethanol and 1.12 L of THF were added. 31 mg bromocresol green and94.26 g sodium cyanoborohydride (1.5 mol) were added. A solutioncontaining 400 mL absolute ethanol and 200 mL of 12 M HCl was thenadded. The reaction mixture was stirred for 30 minutes after additionwas complete. After the starting material was consumed, 0.5 L of 7% aq.NaHCO₃ was added. The reaction mixture was concentrated and diluted with5 L ethyl acetate. The organic layer was washed twice with 2 L of 7% aq.NaHCO₃ and once with 2.5 L of 23% aq. NaCl, the dried over 190 g MgSO₄,filtered, and concentrated to give 447 g of the title compound as athick yellow oil.

EXAMPLE 292F Ethyl2-(4-Methoxypheny)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine3-carboxylate

Into a 22-L flask equipped with overhead stirring, nitrogen inlet, andcondenser was charged ethyl2-(4-methoxyphenyl)-4-(3,4-methylenedioxyphenyl)-pyrrolidine-3-carboxylate(2.223 kg, 6.02 mol). The reaction vessel was degassed with nitrogen.13.2 L of acetonitrile, 3.66 L diisopropylethylamine (2.71 kg, 20.9mol), and 1.567 kg dibutylamidomethyl bromide (6.26 mol) were added. Themixture was refluxed at 78° C. for 17 hrs. After the disappearance ofstarting material, the mixture was concentrated until crystals formed.The solid was filtered and washed with 4 L ethyl acetate (0° C.).Concentrating of the filtrate was continued as above until all volatileswere removed. The residue was diluted with 40 L ethyl acetate and washedwith 20 L deionized water. The organic layer was washed with 8 L of 23%aq. NaCl and dried over 0.399 kg MgSO₄ and filtered. Concentration asabove provided 3.112 kg (96% yield) of the title compound as a dark oil.

EXAMPLE 292Gtrans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine3-carboxylate and Preparation of trans,trans2-(4-Methoxyphenyl)-4-(3,4-dioxyphenyl)-pyrrolidine-3-carboxylic AcidEthyl Ester

Into a 35-L reactor equipped with overhead stirring, nitrogen inlet, andcondenser was charged 3.112 kg ethyl2-(4-methoxyphenyl)-4-(3,4-methylenedioxyphenyl)-pyrrolidine3-carboxylate (5.78 mol). 16.4 L of absolute ethanol was added and thereaction vessel was degassed with nitrogen. 0.115 kg of sodium ethoxide(1.69 mol) was added and the mixture was refluxed at 79° C. for 1 hr.The mixture was cooled to 15° C. and 5 L of 7.6 M NaOH solution (38.1mol) was added. The mixture was stirred at 15° C. for 18 hrs. Thesolvent was evaporated and the residue dissolved in 15.8 L of deionizedwater and extracted with 28 L of ether. The ether solution was washedwith 9.5 L deionized water. The aqueous wash was extracted with 3 Lether. 0.340 L of 12 M HCl was added to the aqueous layer. The aqueouslayer was extracted with 24 L of ethyl acetate. The organic layer waswashed with 9 L of 23% aq. NaCl, dried with 0.298 kg MgSO₄, filtered,and concentrated to give 2.132 kg of a dark oil. The oil was trituratedwith 18 L ether. The undesired solids were filtered and saved for lateruse. The mother liquors were concentrated to obtain 1.102 kg of lightfoam. The foam was dissolved in 5.5 L ethyl acetate with heating to 65°C. 14 L hexane was added slowly enough to keep the solution refluxing.The reaction mixture was cooled to 10° C. and filtered. The crystalswere washed with 2 L ether (0° C.) and dried to constant weight in vacuoat 50° C. to give 0.846 kg (43% yield, melting point 119-120) of crudeproduct, which was further purified by normal phase silica gelchromatography.

EXAMPLE 292H Sodiumtrans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine3-carboxylate

Into a 20-L flask was charged trans,trans2-(4-methoxyphenyl)-4-(3,4-methyledioxyphenyl)-1-(N,N-dibutylamino-carbonylmethyl) pyrrolidine 3-carboxylic acid (0.927 kg, 1.819 mol). A solutionof 0.0720 kg NaOH (1.80 mol) dissolved in 4.65 L methanol was added. Thereaction mixture was concentrated to an oil. Pentane (4 L) was added andthe solution concentrated again. Pentane (4 L) was added again andconcentration of this solution gave a light tan foam. The foam was driedin vacuo at 50° C. to a constant weight of 0.937 kg (97% yield) of thetitle compound.

EXAMPLE 293trans-trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[decahydroisoquinolin-2-carbonylmethyl]-pyrrolidine-3-carboxylicAcid

The title compound was prepared using the procedures described inexample 1. NMR (CD₃OD, 300 MHz) shows a mixture of isomers. MS (DCl/NH₃)m/z 521. Anal calcd for C₃₀H₃₆N₂O₆.1.3 TFA: C, 58.54; H, 6.62; N, 4.19 .Found: C, 58.34; H, 5.58; N, 4.00.

EXAMPLE 294trans-trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[3,3-dimethylpiperidinyl-carbonylmethyl]-pyrrolidine-3-carboxylicAcid

The title compound was prepared using the procedures described inexample 1. NMR (CD₃OD, 300 MHz) indicates presence of rotamers. δ 0.84(s, 3H), 0.86 (s, 3H), 1.35-1.6 (m, 4H), 3.83 (s, 3H), 5.96 (s, 2H),6.81 (d, 1H, J=8), 6.90 (dd, 1H, J=1, 8), 7.01 (d, 2H, J=9), 7.03 (s,1H), 7.47 (d, 2H, J=9). MS (DCl/NH₃) m/z 495. Anal calcd forC₂₈H₃₄N₂O₆.1.4 TFA: C, 56.55; H, 5.45; N, 4.28. Found: C, 56.52; H,5.83; N, 4.26.

EXAMPLE 295trans-trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-iso-butoxycarbonylamino)ethyl]-pyrrolidine-3-carboxylicAcid

The title compound was prepared by the methods detailed in Example 61,but substituting propylamine for methylamine in Example 61B and isobutylchloroformate for isobutyryl chloride in Example 61C.

The crude product was purified by trituration with 1:1 diethylether/hexane. The resulting solid was dissolved in CH₃CN and water andlyophilized to give the product as a white solid. ¹H NMR (CDCl₃, 300MHz) δ 0.80 (t, 3H, J=7), 0.92 (m, 3H), 1.43 (h, 2H, J=7 Hz), 1.7-1.9(m, 1H), 2.72 (m, 1H), 2.90 (m, 2H), 3.10 (m, 2H), 3.25 (m, 2H), 3.40(m, 1H), 3.55 (m, 1H), 3.62 (m, 1H), 3.7-3.9 (m, 2H) 3.78 (s, 3H), 5.95(s, 2H), 6.72 (d, 1H, J=8 Hz), 6.82 (m, 3H), 7.00 (s, 1H), 7.30 (d, 2H,J=8 Hz). MS (DCl/NH₃) m/e 527 (M+H)⁺. Anal calcd for C₂₉H₃₈N₂O₆.0.5 H₂O:C, 65.03; H, 7.34; N, 5.23. Found: C, 65.13; H, 6.96; N, 4.95.

EXAMPLE 296trans-trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[1,2,3,4-tetrahydroisoquinolin-2-carbonylmethyl]-pyrrolidine-3-carboxylicAcid

The title compound was prepared using the procedures described inexample 1. NMR (CD₃OD, 300 MHz) indicates presence of rotamers. δ 2.97(m, 2H), 4.68 (s, 3H), 5.97 (s, 2H), 6.83 (d, 1H, J=8), 6.9-7.0 (m, 3H),7.03 (d, 1H, J=2), 7.1-7.3 (m, 4H), 7.4-7.5 (m, 2H). MS (DCl/NH₃) m/z515.

EXAMPLE 297trans-trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-dimethylaminocarbonylaminoethyl]-pyrrolidine-3-carboxylic

The title compound was prepared by the methods detailed in Example 61,but substituting propylamine for methylamine in Example 61B anddimethylcarbamyl chloride for isobutyryl chloride in Example 61C. Thecrude product was purified by preparative HPLC (Vydac μC18) eluting witha 10-70% gradient of CH₃CN in 0.1% TFA. The desired fractions werelyophilized to give the product as a white solid. ¹H NMR (CDCl₃, 300MHz) δ 0.70 (t, 3H, J=7), 1.28 (m, 2H), 2.75 (s, 3H), 2.82 (m, 2H),3.1-3.45 (m, 4H), 3.70 (m, 1H), 3.80 (s, 3H), 3.90 (m, 3H), 4.72 (m,1H), 5.95 (s, 2H), 6.75 (d, 1H, J=8 Hz), 6.87 (m, 3H), 7.05 (s, 1H),7.40 (d, 2H, J=8 Hz). MS (DCl/NH₃) m/e 498 (M+H)⁺. Anal calcd forC₂₇H₃₅N₃O₆.1.25 TFA: C, 55.35; H, 5.71; N, 6.56. Found: C, 55.41; H,5.71; N, 6.41.

EXAMPLE 298trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-propyl-N-(4-nitrobenzenesulfonyl)amino)ethyl)-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 66, the title compound wasprepared as a yellow solid. m.p. 85-87° C. ¹H NMR (CDCl3, 300 MHz) δ0.77 (t, J=7.5 Hz, 3H), 1.38 (sextet, J=7.5 Hz, 2H), 2.20-2.29 (m, 1H),2.57-2.66 (m, 1H), 2.82-3.15 (m, 4H), 3.22 (t, J=7.5 Hz, 2H) 3.38 (dd,J=3 Hz, J=9 Hz, 11H), 3.49-3.57 (m, 1H), 3.59 (d, J=9 Hz, 11H), 3.83 (s,3H), 5.96 (s, 2H), 6.73 (d, J=8 Hz, 1H), 6.82 (dd, J=1 Hz, J=8 Hz, 1H),6.87 (d, J=9 Hz, 2H), 6.98 (d, J=1 Hz, 1H), 7.27 (d, J=9 Hz, 2H), 7.82(d, J=9 Hz, 8.23 (d, J=9 Hz, 2H). MS (DCl/NH₃) m/e 612 (M+H)⁺.

EXAMPLE 299trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-propyl-N-n-pentanesulfonylamino)ethyl)-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 66, the title compound wasprepared as a white solid. m.p. 59-61° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.79(t, J=7.5 Hz, 3H), 0.90 (t, J=6 Hz, 3H), 1.26-1.32 (m, 4H), 1.43(sextet, J=7.5 Hz, 2H), 1.67-1.76 (m, 2H), 2.23-2.32 (m, 1H), 2.70-3.08(m, 7H), 3.15-3.32 (m, 2H), 3.42 (dd, J=3 Hz, J=9 Hz, 1H), 3.52-3.57 (m,1H), 3.63 (d, J=9 Hz, 1H), 3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=7.5Hz, 1H), 6.83 (dd, J=1 Hz, J=7.5 Hz, 1H), 6.87 (d, J=8 Hz, 2H), 7.00 (d,J=1 Hz, 1H), 7.32 (d, J=8 Hz, 2H). MS (DCl/NH₃) m/e 561 (M+H)⁺.

EXAMPLE 300trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-propyl-N-(4-trifluoromethoxybenzenesulfonyl)amino)ethyl)-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 66, the title compound wasprepared as a white solid. m.p.122-124° C. ¹H NMR (CD₃OD, 300 MHz) δ0.75 (t, J=7.5 Hz, 3H), 1.26-1.45 (m, 2H), 2.96-3.08 (m, 2H), 3.23 (bs,2H), 3.35-3.45 (m, 2H), 3.52 (t, J=10 Hz, 1H), 3.81 (d, J=9 Hz, 2H),3.86 (s, 3H), 3.92 (t, J=9 Hz, 1H), 4.63 (d, J=10 Hz, 1H), 5.97 (s, 2H),6.82 (d, J=9 Hz, 1H), 6.93 (dd, J=3 Hz, J=9 Hz, 1H), 7.06-7.08 (m, 3H),7.46 (d, J=9 Hz, 2H), 7.56 (d, J=9 Hz, 2H), 7.89 (d, J=9 Hz, 2H). MS(DCl/NH3), m/e 651 (M+H)⁺.

EXAMPLE 301trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-propyl-N-(2-methyl-2-propenesulfonyl)amino)ethyl)-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 66, the title compound wasprepared as a white solid. m.p. 69-71° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.79(t, J=5 Hz, 3H), 1.93 (sextet, J+7.5 Hz, 2H), 1.92 (s, 3H), 2.25-2.35(m, 1H), 2.68-2.77 (m, 1H), 2.85-3.28 (m, 7H), 3.40 (d, J=9 Hz, 1H),3.52-3.68 (m, 2H), 3.66 (d, J=9 Hz, 1H), 3.80 (s, 3H), 4.92 (s, 1H),5.07 (s, 1H), 5.97 (s, 2H), 6.74 (d, J=7 Hz, 1H), 6.82-6.89 (m, 3H),7.01 (s, 1H), 7.33 (d, J=9 Hz, 2H). MS (DCl/NH₃), m/e 545 (M+H)⁺.

EXAMPLE 302trans-trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-ethylpiperidinyl-carbonylmethyl]-pyrrolidine-3-carboxylicAcid

The title compound was prepared using the procedures described inexample 1. NMR (CD₃OD, 300 MHz) shows a mixture of isomers. δ 0.75 (t,3H, J=7), 1.4-1.7 (m, 8H), 3.84 (s, 3H), 5.96 (s, 2H), 6.83 (d, 1H,J=8), 6.91 (d, 1H, J=8), 7.0-7.1 (m, 3H), 7.52 (d, 2H, J=9). MS(DCl/NH₃) m/z 495. Anal calcd for C₂₈H₃₄N₂O₆.1.6 TFA: C, 55.35; H, 5.30;N, 4.14. Found: C, 55.26; H, 5.37; N, 4.01.

EXAMPLE 303trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-propyl-N-(2-methylpropanesulfonyl)amino)ethyl)-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 66, the title compound wasprepared as a white solid. m.p. 72-73° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.82(t, J=7.5 Hz, 3H), 1.04 (d, J=6 Hz, 6H), 1.44 (q, J=7.5 Hz, 2H),2.15-2.33 (m, 2H), 2.57-2.75 (m, 2H), 2.84-3.08 (m, 3H), 3.12-3.21 (m,1H), 3.23-3.45 (m, 1H), 3.43 (d, J=11 Hz, 1H), 3.55-3.62 (m, 1H), 3.66(d, J=9 Hz, 1H), 3.80 (s, 3H), 5.95 (s, 2H), 6.75 (d, J=9 Hz, 1H), 6.83(dd, J=1 Hz, J=9 Hz, 1H), 6.87 (d, J=9 Hz, 2H), 7.02 (d, J=1 Hz, 1H),7.33 (d, J=9 Hz, 2H). MS (DCl/NH₃) m/e 547 M+H)⁺.

EXAMPLE 304trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-propyl-N-heptanesulfonylamino)ethyl)-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 66, the title compound wasprepared as a white solid. m.p.58-59° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.80(t, J=7.5 Hz, 3H), 0.88 (t, J=7 Hz, 3H), 1.23-1.36 (m, 8H), 1.94 (q,J=7.5 Hz, 2H), 1.71 (quintet, J=7 Hz, 2H), 2.23-2.32 (m, 1H), 2.70-3.09(m, 7H), 3.13-3.32 (m, 2H), 3.43 (dd, J=3 Hz, J=9 Hz, 1H), 3.52-3.58 (m,1H), 3.65 (d, J=9 Hz, 1H), 3.80 (s, 3H), 5.96 (s, 2H), 6.73 (d, J=7 Hz,1H), 6.83 (dd, J=1 Hz, J=7 Hz, 1H), 6.87 (d, J=9 Hz, 2H), 7.01 (d, J=1Hz, 1H), 7.32 (d, J=9 Hz, 2H). MS (DCl/NH₃) m/e 589 M+H)⁺.

EXAMPLE 305trans-trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-ethyl-N-ethoxycarbonylamino)ethyl]-pyrrolidine-3-carboxylicAcid

Prepared by the methods detailed in Example 61, but substitutingethylamine for methylamine in Example 61B and ethyl chloroformate forisobutyryl chloride in Example 61C. The crude product was purified bypreparative HPLC (Vydac μC18) eluting with a 10-70% gradient of CH₃CN in0.1% TFA. The desired fractions were lyophilized to give the product asa white solid. ¹H NMR (CDCl₃, 300 MHz) δ 0.90 (t, 3H, J=7), 1.22 (m,3H), 3.0-3.2 (m, 4H), 3.42 (m, 2H), 3.78 (s, 3H), 3.82 (m, 4H), 4.10 (q,2H, J=7 Hz), 3.5 (br s, 1H), 5.97 (dd, 2H, J=1, 7 Hz), 6.72 (d, 1H, J=8Hz), 6.84 (m, 3H), 7.00 (s, 1H), 7.42 (d, 2H, J=8 Hz). MS (DCl/NH₃) m/e485 (M+H)⁺. Anal calcd for C₂₆H₃₂N₂O₇.1.2 TFA: C, 54.90; H, 5.39; N,4.51. Found: C, 55.01; H, 5.36; N, 4.56.

EXAMPLE 306trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-propyl-N-hexanesulfonylamino)ethyl)-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 66, the title compound wasprepared as a white solid. m.p.59-60° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.80(t, J=7.5 Hz, 3H), 0.89 (t, J=7 Hz, 3H), 1.25-1.36 (m, 6H), 1.53(sextet, J=7.5 Hz, 2H), 1.72 (quintet, J=7 Hz, 2H), 2.23-2.32 (m, 1H),2.72-3.08 (m, 7H), 3.15-3.32 (m, 2H), 3.43 (d, J=9 Hz, 1H), 3.55-3.62(m, 1H), 3.65 (d, J=10 Hz, 1H), 3.80 (s, 3H), 5.96 (s, 2H), 6.74 (d,J=7.5 Hz, 1H), 6.82 (d, J=7.5 Hz,1H), 6.87(d, J=9 Hz, 2H), 7.01(s, 1H),7.32(d, J=9 Hz,2H). MS (DCl/NH₃), m/e 575 (M+H)⁺.

EXAMPLE 307trans-trans-2-(4-Ethylphenyl)-4-(1,3-benzodioxol-5-yl)-1-[N,N-di(n-butyl)aminocarbonylmethyl]-pyrrolidine-3-carboxylicAcid.

The title compound was prepared using the procedures described inexamples 1 and 49, substituting ethyl 4-ethylbenzoylacetate (prepared bythe method of Krapcho et al., Org. Syn. 47, 20 (1967) starting with4′-ethylacetophenone) in procedure 49B. NMR (CDCl₃, 300 MHz) δ 7.31 (2H,d, J=8 Hz), 7.16 (2H, d, J=8 Hz), 7.03 (1H, d, J=3 Hz), 6.86 (1H, dd,J=8&3 Hz), 6.73 (1H, d, J=9 Hz), 5.94 (1H, d, J=4 Hz), 5.92 (1H, d, J=4Hz), 3.77 (1H, d, J=9 Hz), 3.60 (1H, m), 3.53-3.23 (5H, m), 3.13-2.90(4H, m), 2.73 (1H, d, J=14 Hz), 2.62 (2H, q, J=9 Hz), 1.45 (2H, m),1.40-1.10 (6H, m), 1.02 (2H, m), 0.87 (3H, t, J=7 Hz), 0.78 (3H, t, J=7Hz). m/e (DCl, NH₃) 509 (MH+) Anal.calc. for C₃₀H₄₀N₂O₅ C, 70.84, H,7.93, N, 5.51. Found C, 70.80, H, 7.85, N, 5.25.

EXAMPLE 308trans-trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-(2-chloroethoxy)carbonylamino)ethyl]-pyrrolidine-3-carboxylicAcid

Prepared by the methods detailed in Example 61, but substitutingpropylamine for methylamine in Example 61 B and 2-chloroethylchloroformate for isobutyryl chloride in Example 61C. The crude productwas purified by trituration with 1:1 diethyl ether/hexane. The resultingsolid was dissolved in CH₃CN and water and lyophilized to give theproduct as a white solid. ¹H NMR (CDCl₃, 300 MHz) δ 0.80 (t, 3H, J=7),1.22 (m, 3H), 2.15 (m, 1H), 2.75 (m, 1H), 2.85 (m, 1H), 3.1 (m, 2H),3.25 (m, 2H), 3.5 (m, 3H), 3.65 (m, 2H), 3.80 (s, 3H), 4.18 (m, 1H),4.30 (m, 1H), 5.98 (s, 2H), 6.72 (m, 1H), 6.82 (m, 3H), 7.00 (m, 1H),7.30(m, 2H). MS (DCl/NH₃) m/e 533 (M+H)⁺. Anal calcd for C₂₇H₃₃N₂O₇Cl:C, 60.84; H, 6.24; N, 5.26. Found: C, 60.48; H, 6.04; N, 5.10.

EXAMPLE 309trans-trans-2-(2-Methoxyethyl)-4-(1,3-benzodioxol-5-yl)-1-[N,N-di(n-butyl)aminocarbonylmethyl]-pyrrolidine-3-carboxylicAcid

The title compound was prepared using the procedures described inexample 1, substituting ethyl 5-methoxy-3-oxopentanoate for ethyl4-methoxybenzoylacetate in Example 1A. The title compound is a yellowfoam. ¹H NMR (CDCl₃, 300 MHz) δ 0.91 (t, J=7 Hz) and 0.95 (t, J=7 Hz, 6Htotal), 1.28-1.41 (br m, 4H), 1.45-1.63 (br m, 4H), 2.00-2.20 (br m,2H), 3.06 (br t, J=9 Hz, 1H), 3.30 (s) and 3.20-3.68 (br m, 11H total),3.72-4.10 (br m, 4H), 5.92 (s, 2H), 6.72 (d, J=8.5 Hz, 1H), 6.82 (dd,J=1.5, 8.5 Hz, 1H), 6.91 (d, J=1.5 Hz, 1H); MS (FAB) m/e 463 (M+H)⁺.Anal calcd for C₂₅H₃₈N₂O₅.H₂O: C, 62.48; H, 8.39; N, 5.83. Found: C,62.13; H, 8.15; N, 5.69.

EXAMPLE 310trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-ethyl-N-n-pentanesulfonylamino)ethyl)-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 66, the title compound wasprepared as a white solid. m.p.57-58° C. ¹H NMR (CDCl₃, 300MHz) δ0.89(t, J=7 Hz, 3H), 1.06(t, J=7.5 Hz, 3H), 1.26-1.37(m, 4H),1.72(quintet, J=7.5 Hz, 2H), 2.22-2.32(m,1H), 2.71-2.96(m,5H),3.08-3.30(m,4H), 3.95(d, J=9 Hz, 1H), 3.53-3.60(m, 1H), 3.67(d, J=9Hz,1H), 3.80(s, 1H), 5.97(s, 2H), 6.73(d, J=9 Hz, 1H), .6.82(d, J=9 Hz,1 H), 6.88(d, J=9 Hz, 2H),7.02(s, 1H), 7.33(d, J=9 Hz, 2H). MS (CDl/NH₃)m/e 547 (M+H)⁺.

EXAMPLE 311trans-trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[N,N-dicyclohexylaminocarbonylmethyl]-pyrrolidine-3-carboxylic Acid

The title compound was prepared using the procedures described inexample 1. NMR (CD₃OD, 300 MHz) δ 1.0-2.0 (m, 20H), 3.0-3.1 (m, 2H),3.80 (s, 3H), 5.95 (s, 2H), 6.75 (d, 1H, J=8), 6.86 (dd, 1H, J=2,8),6.95 (d, 2H, J=9), 7.04 (d, 1H, J=2), 7.38 (d, 2H, J=9). MS (DCl/NH₃)m/z 563. Anal calcd for C₃₃H₄₂N₂O₆.0.5 H₂O: C, 69.33; H, 7.58; N, 4.90.Found: C, 69.42; H, 7.29; N, 4.78.

EXAMPLE 312trans-trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-tert-butoxycarbonylamino)ethyl]-pyrrolidine-3-carboxylicAcid

The title compound was prepared using the procedures described inexample 61, substituting propylamine for aqueous methylamine in Example61B and di-tert-butyldicarbonate for isobutyryl chloride in Example 61C.NMR (CD₃OD, 300 MHz) suggests presence of rotamers δ 0.81 (t, 3H, J=7),1.2-1.5 (m, 11H), 3.78 (s, 3H), 5.92 (dd, 2H, J=1,2), 6.74 (d, 1H, J=8),6.84 (dd, 1H, J=2,8), 6.92 (d, 2H, J=9), 6.99 (bd s, 1H), 7.35 (d, 2H,J=9). MS (DCl/NH₃) m/z 527. Anal calcd for C₂₉H₃₈N₂O₇: C, 66.14; H,7.27; N, 5.32. Found: C, 66.05; H, 7.36; N, 5.15.

EXAMPLE 313trans-trans-2-(4-Methoxy-3-fluorophenyl)-4-(1,3-benzodioxol-5-yl)-1-[N,N-di(n-butyl)aminocarbonylmethyl]-pyrrolidine-3-carboxylicAcid

The title compound was prepared using the methods described in examples1 and 43, using 4-methoxy-3-fluoro acetophenone in place of 4-methoxyacetophenone. m.p. 142-143° C. NMR (CDCl₃, 300 MHz) δ 0.82 (t, J=7 Hz,3H), 0.88 (t, J=7 Hz, 3H), 1.03-1.50 (m, 8H), 2.82 (d, J=13 Hz, 1H),2.90-3.13 (m, 4H), 3.20-3.50 (m, 3H), 3.39 (d, J=13H, 1H), 3.55-3.65 (m,1H), 3.82 (d, J=10 Hz, 1H), 3.87 (s, 3H), 5.91 (dd, J=2 Hz, 4 Hz, 2H),6.72 (d, J=8 Hz, 1H), 6.83-6.91 (m, 2H), 6.99 (d, J=2 Hz, 1H), 7.06 (m,2H). Anal calcd for C₂₉H₃₇N₂O₆F: C, 65.89; H, 7.06; N, 5.30 . Found: C,65.82; H, 7.13; N, 5.29.

EXAMPLE 314trans,trans-2-(Propyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-propyl-pentanesulfonylamino)ethyl)pyrrolidine-3-carboxylicAcid EXAMPLE 314A Propyl Pentanesulfonamide

Pentane sulfonyl chloride (687 mg, 4.03 mmol) was dissolved in 5 mLCH₂Cl₂ and added to an ice-cooled solution of n-propylamine (0.40 mL,4.82 mmol) and ethyldiisopropylamine (0.85 mL, 4.88 mmol) in 5 mL CH₂Cl₂under a nitrogen atmosphere. The reaction was stirred at 0° C. for 30min, then at 25° C. for 4 h. The solution was partitioned between 20 mLof 1.0 M aqeous NaHSO₄ and 25 mL CH₂Cl₂. The organic phase was washedsequentially with 25 mL H₂O and 25 mL brine, then dried (Na₂SO₄),filtered, and concentrated in vacuo to provide 739 mg (3.83 mmol, 95%)of the title compound as a white solid. TLC (25% EtOAc-hexane) Rf 0.23;¹H NMR (CDCl₃, 300 MHz) δ 0.92 (t, J=7 Hz, 3H), 0.97 (t, J=7 Hz, 3H),1.28-1.50 (br m, 4H), 1.52-1.68 (m, 2H), 1.75-1.90 (br m, 2H), 2.98-3.06(m, 2H), 3.08 (q, J=6 Hz, 2H), 4.10-4.23 (br m, 1H); MS (DCl/NH₃) m/e211 (M+NH₄)⁺.

EXAMPLE 3149B Ethyltrans,trans-4-(1,3-benzodioxol-5-yl)-1-(2-bromoethyl)-2-propylpyrrolidine-3-carboxylate

The title compound was prepared according the procedure of Example 61A,substituting the compound of Example 94B for the pyrrolidine mixture.

EXAMPLE 314CEthyltrans,trans-2-(Propyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-propyl-pentanesulfonylamino)ethyl)pyrrolidine-3-carboxylate

A solution of the compound of Example 314A (6.6 mg, 34 μmol) in 0.1 mLDMF was treated with sodium hydride (2 mg, 60% oil dispersion, 1.2 mgNaH, 50 μmol). The resulting mixture was stirred at room temperature for15 min, then a solution of the compound of Example 189B (9.0 mg, 22μmol) in 0.1 mL DMF was added, followed b y 0.5 mg oftetra-n-butylammonium iodide. The reaction was sealed under argon andstirred at 60° C. overnight. The reaction was concentrated under highvacuum, and the residue was partitioned between 2 mL of saturatedaqueous NaHCO₃, 1 mL water and 5 mL EtOAc. The organic phase was washedwith 1 mL brine, dried by passing through a plug of Na₂SO₄, and thefiltrate concentrated in vacuo to an oil. The crude product was purifiedby preparative TLC (silica gel, 8×20 cm, 0.25 mm thickness, eluting with20% EtOAc-hexane, providing 8.4 mg (73%) of the title compound as a wax.

EXAMPLE 314Dtrans,trans-4-(1,3-benzodioxol-5-yl)-2-(Propyl)-1-(2-(N-propyl-pentanesulfonylamino)ethyl)pyrrolidine-3-carboxylicAcid

The title compound was prepared according to the procedure of Example71C. ¹H NMR (CDCl₃, 300 MHz) δ 0.88-1.00 (m, 9H), 1.20-1.55 (br m, 6H),1.55-1.68 (m, 3H), 1.70-1.85 (br m, 2H), 1.90-2.16 (br m, 2H), 2.84-3.26(br m, 6H), 3.26-3.90 (br m, 6H), 5.95 (s, 2H), 6.76 (d, J=8 Hz, 1H),6.79 (m, 1H), 6.93 (br s, 1H); HRMS (FAB) calcd for C₂₅H₄₁N₂O₆S(M+H)⁺497.2685, found 497.2679.

EXAMPLE 315trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-propyl-N-dimethylsulfamoylamino)ethyl)-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 66, the title compound wasprepared as a white solid. m.p. 59-61° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.79(t, J=7.5 Hz, 3H), 1.45(sextet, J=7.5 Hz, 2H), 2.22-2.31(m,1H), 2.65(s,6H), 2.70-2.79(m, 1H), 2.85-3.04(m, 4H), 3.09-3.32(m, 2H), 3.40(d, J=9Hz, 1H),3.55 (t, J=9 Hz, 1H), 3.65(d, J=9 Hz, 1H), 3.81(s, 3H), 5.96(s,2H), 6.75(d, J=9 Hz, 1H), 6.83(d, J=9 Hz, 1H), 6.88(d, J=9 Hz, 2H),7.02(s, 1H), 7.34(d, J=9 Hz, 2H). MS (DCl/NH3) m/e534 (M+H)⁺.

EXAMPLE 316trans-trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-[4-methoxyphenyl]sulfonylamino)propyl]-pyrrolidine-3-carboxylicAcid EXAMPLE 316A Ethyl trans-trans and cis-trans2-(4-Methoxyphenyl)-4-(1,3-benzodiox-5-yl)-1-(3-bromopropyl)pyrrolidine-3-carboxylate

A 2:1 mixture of trans-trans and cis-trans ethyl2-(4-methoxyphenyl)-4-(1,3-benzodiox-5-yl)-pyrrolidine-3-carboxylate(4.00 g; prepared according to example 1C), 32 ml dibromopropane, and200 mg sodium iodide, were heated at 100° for 1.25 hrs. The excessdibromopropane was removed in vacuo and the residue was dissolved intoluene. After shaking with potassium bicarbonate, the solution wasdried (Na₂SO₄) and the solution concentrated. The residue waschromatographed on silica gel eluting with 5:1 hexane:EtOAc. yielding5.22 (98%) of the title compound.

EXAMPLE 316B Ethyl trans-trans and cis-trans2-(4-Methoxyphenyl)-4-(1,3-benzodiox-5-yl)-1-(3-propylaminopropyl)pyrrolidine-3-carboxylate

The compound described in Example 316A (5.22 9) was heated at 80° for 2hrs with 35 ml. ethanol, 2.5 g. propylamine and 35 mg. sodium iodide.The solvents were removed in vacuo. The residue was dissolved intoluene, shaken with potassium bicarbonate solution and dried (Na₂SO₄).The solution was concentrated in vacuum to give 4.96 g of the titlecompound as an orange oil. This was used in the next step withoutpurification.

EXAMPLE 316Ctrans-trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-[4-methoxyphenyl]sulfonylamino)propyl]-pyrrolidine-3-carboxylicAcid

Using the method described in example 66, the compound prepared inExample 316B was reacted with 4-methoxybenzenesulfonyl chloride inacetonitrile containing diisopropylethylamine. The resulting product waschromatographed on silica gel (30% EtOAc in hexane), and hydrolyzed tothe title compound by the method of example 1D. NMR (CDCl₃, 300 MHz) δ0.83 (t, J=7 Hz, 3H), 1.40-1.52 (m, 2H), 1.56-1.70 (m, 2H), 2.00-2.11(m, 1H), 2.40-2.51 (m, 1H), 2.69-2.78 (m, 1H), 2.84-3.03 (m, 4H),3.19-3.34 (m, 2H), 3.48-3.59 (m, 2H), 3.80 (s, 3H), 3.86 (s, 3H), 5.95(s, 2H), 6.74 (d, J=8 Hz, 1H), 6.85 (d, J=8 Hz, 3H), 6.93 (d, J=8 Hz,2H), 7.02 (d, J=2 Hz, 1H), 7.29 (d, J=8 Hz, 2H), 7.69 (d, J=8 Hz, 2H).Anal calcd for C₃₂H₃₈N₂O₈S: C, 62.93; H, 6.27; N, 4.59. Found: C, 62.97;H, 6.39; N, 4.45.

EXAMPLE 317trans-trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-propylsulfonylamino)propyl]-pyrrolidine-3-carboxylicAcid

Using the method described in example 66, the propylamino compoundprepared in Example 316B was reacted with propanesulfonyl chloride inacetonitrile containing diisopropylethylamine. The resulting product waschromatographed on silica gel (30% EtOAc in hexane) and hydrolyzed tothe title compound by the method of example 1D. NMR (CDCl₃, 300 MHz) δ0.85 (t, J=7 Hz, 3H), 1.02 (t, J=7 Hz, 3H), 1.47-1.60 (m, 2H), 1.65-1.85(m, 4H), 2.04-2.16 (m, 1H), 2.42-2.57 (m, 1H), 2.72-3.11 (m, 5H),3.25-3.41 (m, 2H), 3.50-3.62 (m, 2H), 3.80 (s, 3H), 5.85 (s, 2H), 6.72(d, J=8 Hz, 1H), 6.80-6.90 (m, 3H), 7.02 (d, J=2 Hz, 1H), 7.30 (d, J=9Hz, 2H). Anal calcd for C₂₈H₃₈N₂O₇S: C, 61.52; H, 7.01; N, 5.12. Found:C, 61.32; H, 7.01; N, 5.01.

EXAMPLE 318trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)1-(2-(N-propyl-N-pentanesulfonylamino)ethyl)-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 313 and Example 66, the titlecompound was prepared as a white solid. m.p. 66-68° C. ¹H NMR (CDCl₃,300MHz) δ 0.81(t,J=7.5 Hz, 3H), 0.89(t, J=7 Hz, 3H), 1.26-1.35(m, 4H),1.45(sextet, J=7.5 Hz, 2H), 1.68-1.76(m, 2H), 2.25-2.33(m, 1H),2.72-2.92(m, 5H), 2.97-3.12(m, 2H), 3.16-3.33(m,2H), 3.43(dd, J=3 Hz,J=9Hz, 1H), 3.53-3.60(m, 1H), 3.66(d, J=10 Hz, 1H), 3.88(s, 3H), 5.95(s,2H), 6.74(d, J=8 Hz, 1H), 6.82(dd, J=1 Hz,J=8 Hz, 1H), 6.92(t, J=8Hz,1H), 6.97(d, J=1 Hz, 1H), 7.12(d, J=8 Hz, 1H), 7.18(dd, J=1 Hz,J=12Hz, 1H). MS (DCl/NH₃) m/e 579 (M+H)⁺.

EXAMPLE 319trans-trans-2-(4—Pyridinyl)-4-(1,3-benzodioxol-5-yl)-1-[N,N-di(n-butyl)aminocarbonylmethyl]-pyrrolidine-3-carboxylicAcid

The title compound was prepared using the methods described in examples1 and 43, using methyl 3-oxo-3-(4-pyridyl)propanoate (J. Am. Chem. Soc.1993, 115, 11705) in place of ethyl (4-methoxybenzoyl)acetate. m.p.131-132° C. NMR (CDCl₃, 300 MHz) δ 0.82 (t, J+7 Hz, 3H), 0.88 (t, J=7Hz, 3H), 1.05-1.50 (m, 8H), 2.90 (dd, J=7 Hz, 9 Hz, 1H), 2.97 (d, J=13Hz, 1H), 3.00-3.25 (m, 4H), 3.32 (m, 1H), 3.39 (d, J=13 Hz, 1H),3.45-3.52 (m, 1H), 3.67-3.78 (m, 1H), 4.10 (d, J=9 Hz, 1H), 5.92 (dd,J=2 Hz, 4 Hz, 2H), 6.75 (d, J=9 Hz, 1H), 6.90 (dd, J=9 Hz, 2Hz, 2 Hz,1H), 7.02 (d, J=2 Hz, 1H), 7.45 (d, J=8 Hz, 2H), 8.50 (d, J=8 Hz, 2H).Anal calcd for C₂₇H₃₅N₃O₅: C, 67.34; H, 7.33; N, 8.73 . Found: C, 67.39;H, 7.45; N, 8.61.

EXAMPLE 320trans-trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-diethylaminocarbonylamino)ethyl]-pyrrolidine-3-carboxylicAcid

The title compound was prepared using the procedures described inexample 61, substituting propylamine for aqueous methylamine in Example61B and diethylcarbamyl chloride for isobutyryl chloride in Example 61C.NMR (CD₃OD, 300 MHz) δ 0.74 (t, 3H, J=7), 1.09 (t, 6H, J=7), 1.33 (m,2H), 3.17 (q, 4H, J=7), 3.78 (s, 3H), 4.04 (m, 1H), 5.93 (s, 2H), 6.86(d, 1H, J=8), 7.06 (dd, 1H, J=2,8), 6.94 (d, 2H, J=9), 7.04 (d, 1H,J=2), 7.40 (d, 2H, J=9). MS (DCl/NH₃) m/z 526. Anal calcd forC₂₉H₃₉N₃O₆. 0.1 TFA: C, 65.31; H, 7.34; N, 7.82 . Found: C, 65.33; H,7.43; N, 8.14.

EXAMPLE 321trans-trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[3,5-dimethylpiperidinyl-carbonylmethyl]-pyrrolidine-3-carboxylicAcid

The title compound was prepared using the procedures described inexample 1. NMR (CD₃OD, 300 MHz) shows mixture of isomers. δ 0.88 (d, 3H,J=7), 0.93 (d, 3H, J=7), 3.82 (s, 3H), 5.95 (s, 2H), 6.82 (d, 1H, J=8),6.89 (dd, 1H, J=1,8), 7.00 d, 2H, J=9), 7.03 (m, 1H), 7.47 (d, 2H, J=9).MS (DCl/NH₃) m/z 495.

EXAMPLE 322trans-trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[N,N-di(s-butyl)aminocarbonylmethyl]-pyrrolidine-3-carboxylicAcid

The title compound was prepared using the procedures described inexample 1. NMR (CD₃OD, 300 MHz) suggests a mixture of isomers. δ 0.83(t, 6H, J=8), 1.27 (d, 6H, J=7), 1.6 (m, 2H), 3.79 (s, 3H), 5.93 (s,2H), 6.75 (d, 1H, J=8), 6.86 (d, 1H, J=8), 6.94 (d, 2H, J=9), 7.03 (d,1H, J=2), 7.35 (d, 2H, J=9). MS (DCl/NH₃) m/z 511.

EXAMPLE 323trans-trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[N-(2-Methylphenyl)-N-butylaminocarbonylmethyl]-pyrrolidine-3-carboxylic Acid

The title compound was prepared using the procedures described inexample 1. MS (DCl/NH₃) m/z 545. Anal calcd for C₃₂H₃₆N₂O₆.0.9 H₂O: C,68.53; H, 6.79; N, 4.99 . Found: C, 68.56; H, 6.62; N, 4.71.

EXAMPLE 324trans-trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[N-(3-Methylphenyl)-N-butylaminocarbonylmethyl]-pyrrolidine-3-carboxylic Acid

The title compound was prepared using the procedures described inexample 1. NMR (CD3OD, 300 MHz) δ 0.88 (t, 3H, J=7), 1.2-1.5 (m, 4H),2.31 (s, 3H), 2.8 (m, 2H), 3.14 (t, 1H, J=10), 3.3 (m, 1H), 3.44 (dd,1H, J=5,10), 3.53 (m, 1H), 3.60 (t, 2H, J=7), 3.79 (s, 3H), 3.82 (m,1H), 5.93 (s, 2H), 6.74 (d, 1H, J=8), 6.8-6.9 (m, 5H), 7.06 (d, 1H,J=2), 7.09 (d, 2H, J=9), 7.18 (d, 1H, J=7), 7.27 (t, 1H, J=7). MS(DCl/NH₃) m/z 545. Anal calcd for C₃₂H₃₆N₂O₆.0.8 H₂O: C, 68.75; H, 6.78;N, 5.01. Found: C, 68.70; H, 6.67; N, 4.85.

EXAMPLE 325trans,trans-4-(1,3-Benzodioxol-5-yl)-2-(benzyloxymethyl)-1-((N,N-dibutylaminocarbonylmethyl)pyrrolidine-3-carboxylicAcid EXAMPLE 325A Ethyltrans,trans-4-(1,3-Benzodioxol-5-yl)-2-(benzyloxymethyl)-1-((N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylate

The procedures of Example 1A-1D were followed, substituting ethyl4-benzyloxy-3-oxobutyrate for 4-methoxybenzoylacetate in Example 1A, toafford the title compound as a colorless oil. TLC (30% EtOAc-hexane) Rf0.18; ¹H NMR (CDCl₃, 300 MHz) δ 0.88 (t, J=7 Hz, 6H), 1.17 (t, J=7 Hz,3H), 1.20-1.34 (br m, 4H), 1.40-1.56 (br m, 3H), 2.85 (t, J=8 Hz, 1H),2.98-3.30 (m, 5H), 3.39-3.60 (m, 3H), 3.64-3.75 (m, 2H), 3.92 (d, J−14Hz, 1H), 4.10 (two overlapping q, J=6.5 Hz, 2H), 4.53 (s, 2H), 5.91 (m,2H), 6.69 (d, J=9Hz, 1H), 6.77 (dd, J=1.5, 9 Hz, 1H), 6.91 (d, J=1.5 Hz,1H); MS (DCl/NH₃) m/e 553 (M+H)⁺.

EXAMPLE 325Btrans,trans-4-(1,3-Benzodioxol-5-yl)-2-(benzyloxymethyl)-1-((N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylicAcid

The title compound was prepared according to the procedure of Example71C, as a colorless glass. TLC (5% MeOH-CH₂Cl₂) Rf 0.13; ¹H NMR (CDCl₃,300 MHz) δ 0.86 (t, J=7 Hz), and 0.90 (t, J=7 Hz, 6H total), 1.15-1.52(br m, 8H), 2.96-3.35 (br m, 5H), 3.50-3.75 (br m, 2H), 3.80 (dd, J=3,13 Hz, 1H), 3.88-4.40 (br m, 6H), 4.45 (AB, 2H), 5.90 (s, 2H), 6.70 (d,J=8Hz, 1H), 6.84 (dd, J=1,8 Hz, 1H), 6.93 (d, J=1 Hz, 1H), 7.28-7.39 (m,5H); MS (DCl/NH₃) m/e 524 (M+H)⁺.

EXAMPLE 326trans,trans-4-(1,3-Benzodioxol-5-yl)-2-(hydroxymethyl)-1-((N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylicAcid EXAMPLE 326AEthyltrans,trans-4-(1,3-Benzodioxol-5-yl)-2-(hydroxymethyl)-1-((N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylate

The resultant product from Example 325A (128 mg, 0.232 mmol) and 25 mgof 20% Pd(OH)₂ on charcoal in 7 mL EtOH was stirred under 1 atm hydrogenfor 48 h. The mixture was filtered through a plug of celite, and thecatalyst was washed with 2×10 mL EtOH, then the combined filtrate andwashes were concentrated under reduced pressure to afford the crudeproduct. Purification by flash chromatography (40% EtOAc-hexane)provided the title compound.

EXAMPLE 326Btrans,trans-4-(1,3-Benzodioxol-5-yl)-2-(hydroxymethyl)-1-((N,N-di(butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylicAcid

The title compound was prepared according to the procedure of Example71C.

EXAMPLE 327trans,trans-4-(1,3-Benzodioxol-5-yl)-2-(N-methylpropenamid-3-yl)-1-((N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylicAcid EXAMPLE 327A Ethyltrans,trans-4-(1,3-Benzodioxol-5-yl)-2-(formyl)-1-((N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylate

The title compound is made by selective oxidation (e.g. using the Swernoxidation with DMSO, oxalyl chloride, ethyldiisopropylamine or using theDess-Martin periodinane) of the compound of Example 326A.

EXAMPLE 327B Ethyltrans,trans-4-(1,3-Benzodioxol-5-yl)-2-(0-tert-butylpropenoat-3-yl)-1-((N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylate

The title compound is produced by condensing the compound of Example327A with tert-butyl triphenylphosphoranylidine acetate in CH₂Cl₂solution.

EXAMPLE 327C Ethyl trans,trans-4-(1,3-Benzodioxol-5-yl)-2-(propenoicacid-3-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylate

The title compound is produced by reacting the compound of Example 327Bwith trifluoacetic acid in CH₂Cl₂ (1:1).

EXAMPLE 327D Ethyltrans,trans-4-(1,3-Benzodioxol-5-yl)-2-(N-methylpropenamid-3-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylate

The title compound is produced by condensing the compound of Example327C with methylamine hydrochloride in the presence of a carbodiimide(e.g. N-ethyl-N-(3-dimethylamino)propylcarbodiimide, DCC).

EXAMPLE 327Etrans,trans-4-(1,3-Benzodioxol-5-yl)-2-(N-methylpropenamid-3-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylicAcid

The title compound is produced by reacting the compound of Example 327Dwith lithium hydroxide according to the procedure of Example 71C.

EXAMPLE 328trans,trans-4-(1,3-Benzodioxol-5-yl)-2-(1-hydroxy-2-propen-3-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylicAcid EXAMPLE 328A Ethyltrans,trans-4-(1,3-Benzodioxol-5-yl)-2-(1-hydroxy-2-propen-3-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylate

The title compound is produced by reacting the compound of Example 327Cwith borane methyl sulfide complex.

EXAMPLE 328Btrans,trans-4-(1,3-Benzodioxol-5-yl)-2-(1-hydrox-2-propen-3-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylicAcid

The title compound is produced by condensing the compound of Example328A with lithium hydroxide according to the procedure of Example 71C.

EXAMPLE 329trans,trans-4-(1,3-Benzodioxol-5-yl)-2-(N-benzylaminomethyl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylicAcid EXAMPLE 329A Ethyltrans,trans-4-(1,3-Benzodioxol-5-yl)-2-(N-benzylaminomethyl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylate

The title compound is produced by condensing the compound of Example327A with benzylamine in the presence of sodium cyanoborohydride inethanol.

EXAMPLE 329Btrans,trans-4-(1,3-Benzodioxol-5-yl)-2-(N-benzylaminomethyl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylicAcid

The title compound is produced by reacting the compound of Example 329Awith lithium hydroxide according to the procedure of Example 71C.

EXAMPLE 330trans,trans-4-(1,3-Benzodioxol-5-yl)-2-(N-acetyl-N-benzylaminomethyl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylicAcid EXAMPLE 330A Ethyltrans,trans-4-(1,3-Benzodioxol-5-yl)-2-(N-acetyl-N-benzylaminomethyl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylate

The title compound is produced by reacting the compound of Example 3294Awith acetic anhydride in the presence of pyridine or triethylamine.

EXAMPLE 330B trans,trans-4-(1,3-Benzodioxol-5-yl)-2-(N-acetyl-N-benzylaminomethyl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylicAcid

The title compound is produced by reacting the compound of Example 330Awith lithium hydroxide according to the procedure of Example 71C.

EXAMPLE 331trans,trans-4-(1,3-Benzodioxol-5-yl)-2-(ethynyl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylicAcid EXAMPLE 331A Ethyl trans,trans-4-(1,3-Benzodioxol-5-yl)-2-(ethynyl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylate

The title compound is made by employing the procedure of Corey and Fuchs(Tetrahedron Lett. 1972, 3769-72), using the compound of Example 327A.

EXAMPLE 331Btrans,trans-4-(1,3-Benzodioxol-5-yl)-2-(ethynyl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-³-carboxylicAcid

The title compound is produced by reacting the compound of Example 331Awith lithium hydroxide according to the procedure of Example 71C.

EXAMPLE 332trans,trans-4-(1,3-Benzodioxol-5-yl)-2-(1-pentynyl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylicAcid EXAMPLE 332A Ethyltrans,trans-4-(1,3-Benzodioxol-5-yl)-2-(pentynyl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylate

The title compound is made by palladium-catalyzed coupling of thecompound of Example 206A and propyl iodide, employing the procedure ofTaylor, et. al. (J. Org. Chem. 1989, 54(15), 3618-24).

EXAMPLE 332Btrans,trans-4-(1,3-Benzodioxol-5-yl)-2-(1-pentynyl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylicAcid

The title compound is produced by reacting the compound of Example 332Awith lithium hydroxide according to the procedure of Example 71C.

EXAMPLE 333trans-trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(2,6-dioxopiperidinyl)ethyl}-pyrrolidine-3-carboxylicAcid

The compound of example 61 A is added to a solution of the sodium saltof glutarimide in dimethylformamide. After stirring 24 hours, water isadded and the mixture is extracted with ether. The resultant glutarimideis hydrolyzed to the title compound by the method of example 1D.

EXAMPLE 334trans-trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[N,N-diphenylaminocarbonylmethyl]-pyrrolidine-3-carboxylicAcid

The title compound was prepared according to the procedures described inExample 1. ¹H NMR (300 MHz, CD₃OD) δ 2.83 (dd, 1, J=8.1, 9.7), 2.99 (d,1, J=15.4), 3.19 (t, 1, J=9.5), 3.49 (d, 1, J=15.3), 3.51 (dd, 1, J=4.6,9.5), 3.57 (m, 1), 3.79 (s, 3), 3.85 (d, 1, J=9.5), 5.90 (s, 2), 6.71(d, 1, J=8.0), 6.84 (m, 3), 7.04 (d, 1, J=1.6), 7.14-7.16 (m, 6),7.19-7.34 (m, 6); MS (DCl/NH₃) m/z 551; Anal Calcd forC₃H₃₀N₂O₆.0.65H₂O.0.35C₂H₅OCOCH₃: C, 69.77, H, 5.77, N, 4.76. Found: C,69.75, H, 5.55, N, 4.64.

EXAMPLE 335trans-trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[N,N-diisopropylaminocarbonylmethyl-pyrrolidine-3-carboxylicAcid

The title compound was prepared according to the procedures described inExample 1. ¹H NMR (300 MHz, CD₃OD) δ 0.95 (d, 3, J=6.5), 1.24 (d, 3,J=6.4), 1.30 (d, 6, J=6.8), 2.85 (d, 1, J=12.5), 3.04 (dd, 1, J=8.1,9.8), 3.14 (t, 1, J=9.7), 3.32-3.55 (m, 3), 3.63 (m, 1), 5.92 (s, 2),6.75 (d, 1, J=8.1), 6.85 (dd, 1, J=1.7, 8.1), 6.93 (m, 2), 7.02 (d, 1,J=1.7), 7.35 (m, 2). MS (DCl/NH₃) m/z 483. Anal Calcd for C₂₇H₃₄N₂O₆.0.65 EtOAc: C, 65.86, H, 7.32, N, 5.19. Found: C, 5.74, H, 7.26, N,5.52.

EXAMPLE 336trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-N-propyl-N-butanesulfonylamino)ethyl)-pyrrolidine-3-carboxylicAcid

Using the procedures described in Example 313 and Example 66, the titlecompound was prepared as a white solid. m.p.65-66° C. ¹H NMR (CDCl3, 300MHz) δ 0.82(t, J=7.5 Hz, 3H), 0.92(t, J=7.5 Hz, 3H), 1.34-1.52(m, 4H),1.72(quintet, J=7.5 Hz,2H), 2.25-2.35(m,1H), 2.72-2.94(m, 5H),2.97-3.12(m, 2H), 3.19-3.46(m, 2H), 3.44(d, J=9 Hz,1H), 3.53-3.60(m,1H), 3.67(d, J=9 Hz, 1H), 3.89(s, 3H), 5.95(s, 2H), 6.74(d, J=8 Hz, 1H),6.82(d, J=8 Hz, 1H), 6.92(t, J=9 Hz, 1H), 6.97(s, 1H), 7.12(d, J=9 Hz,1H), 7.18(d, J=12 Hz, 1H). MS (DCl/NH3) m/e 565 (M+H)⁺.

EXAMPLE 337

Using methods described in the above examples, the compounds disclosedin Table 1 can be prepared.

TABLE 1

R 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

94.

95.

96.

97.

98.

99.

100.

101.

102.

103.

104.

105.

106.

107.

108.

109.

110.

111.

112.

113.

114.

115.

116.

117.

118.

119.

120.

121.

122.

123.

124.

125.

126.

127.

128.

129.

130.

131.

132.

133.

134.

135.

136.

137.

138.

139.

140.

141.

142.

143.

144.

145.

146.

147.

148.

149.

150.

151.

152.

153.

154.

155.

156.

157.

158.

159.

160.

161.

162.

163.

164.

165.

166.

167.

168.

169.

170.

171.

172.

173.

174.

175.

176.

177.

178.

179.

180.

181.

182.

183.

184.

185.

186.

187.

188.

189.

190.

191.

192.

193.

194.

195.

196.

197.

198.

199.

200.

201.

202.

203.

204.

205.

206.

207.

208.

209.

210.

211.

212.

213.

214.

215.

216.

217.

218.

219.

220.

221.

222.

223.

224.

225.

226.

227.

228.

229.

230.

231.

232.

233.

234.

235.

236.

237.

238.

239.

240.

241.

242.

243.

244.

245.

246.

247.

248.

249.

250.

251.

252.

253.

254.

255.

256.

257.

258.

259.

260.

261.

262.

263.

264.

265.

266.

267.

268.

269.

270.

271.

272.

273.

274.

275.

276.

277.

278.

279.

280.

281.

282.

283.

284.

285.

286.

287.

288.

289.

290.

291.

292.

293.

294.

295.

296.

297.

298.

299.

300.

301.

302.

303.

304.

305.

306.

307.

308.

309.

310.

311.

312.

313.

314.

315.

316.

317.

318.

319.

320.

321.

322.

323.

324.

325.

326.

327.

328.

329.

330.

331.

332.

333.

334.

335.

336.

337.

338.

339.

340.

341.

342.

343.

344.

345.

346.

347.

348.

349.

350.

351.

352.

353.

354.

355.

356.

357.

358.

359.

360.

361.

362.

363.

364.

365.

366.

367.

368.

369.

370.

371.

372.

373.

374.

375.

376.

377.

378.

379.

380.

381.

382.

383.

384.

385.

386.

387.

388.

389.

390.

391.

392.

393.

394.

395.

396.

397.

398.

399.

400.

401.

402.

403.

404.

405.

406.

407.

408.

409.

410.

411.

412.

413.

414.

415.

416.

417.

418.

419.

420.

421.

422.

423.

424.

425.

426.

427.

428.

429.

430.

431.

432.

433.

434.

435.

436.

437.

438.

439.

440.

441.

442.

443.

444.

445.

446.

447.

448.

449.

450.

451.

452.

453.

454.

455.

456.

457.

458.

459.

460.

461.

462.

463.

464.

465.

466.

467.

468.

469.

470.

471.

372.

473.

474.

475.

476.

477.

478.

479.

480.

481.

482.

483.

484.

485.

486.

487.

488.

489.

490.

491.

492.

493.

494.

495.

496.

497.

498.

499.

500.

501.

502.

503.

504.

505.

506.

507.

508.

509.

510.

511.

512.

513.

514.

515.

516.

517.

518.

519.

520.

521.

522.

523.

524.

525.

526.

527.

528.

529.

530.

531.

532.

533.

534.

535.

536.

537.

538.

539.

540.

541.

542.

543.

544.

545.

546.

547.

548.

549.

550.

551.

552.

553.

554.

555.

556.

557.

558.

559.

560.

561.

562.

563.

564.

565.

566.

567.

568.

569.

570.

571.

572.

573.

574.

575.

576.

577.

578.

579.

580.

581.

582.

583.

584.

585.

586.

587.

588.

589.

590.

591.

592.

593.

594.

595.

596.

597.

598.

599.

600.

601.

602.

603.

604.

605.

606.

607.

608.

609.

610.

611.

612.

613.

614.

615.

616.

617.

618.

619.

620.

621.

622.

623.

624.

625.

626.

627.

628.

629.

630.

631.

632.

633.

634.

635.

636.

637.

638.

639.

640.

641.

642.

643.

644.

645.

646.

647.

648.

649.

650.

651.

652.

653.

654.

655.

656.

657.

658.

659.

660.

661.

662.

663.

664.

665.

666.

667.

668.

669.

670.

671.

672.

673.

674.

675.

676.

677.

678.

679.

680.

681.

682.

683.

684.

685.

686.

687.

688.

689.

690.

691.

692.

693.

694.

695.

696.

697.

698.

699.

700.

701.

702.

703.

704.

705.

706.

707.

708.

709.

710.

711.

712.

713.

714.

715.

EXAMPLE 338

Using methods described in the above examples, compounds comprising aparent structure selected from those disclosed in Table 2A and an Rsubstituent selected from those disclosed in Table 2B can be prepared.

TABLE 2A 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

94.

95.

96.

97.

98.

99.

100.

101.

102.

103.

104.

105.

106.

107.

108.

109.

110.

111.

112.

113.

114.

115.

116.

117.

118.

119.

120.

121.

122.

123.

124.

125.

126.

127.

128.

129.

130.

131.

132.

133.

134.

135.

136.

137.

138.

139.

140.

141.

142.

143.

144.

145.

146.

147.

148.

149.

150.

151.

152.

153.

154.

155.

156.

157.

158.

159.

160.

161.

162.

163.

164.

165.

166.

167.

168.

169.

170.

171.

172.

173.

174.

175.

176.

177.

178.

179.

180.

181.

182.

183.

184.

185.

186.

187.

188.

189.

190.

191.

192.

193.

194.

195.

196.

197.

198.

199.

200.

201.

202.

203.

204.

205.

206.

207.

208.

209.

210.

211.

212.

213.

214.

215.

216.

217.

218.

219.

220.

221.

222.

223.

224.

225.

226.

227.

228.

229.

230.

231.

232.

233.

234.

235.

236.

237.

238.

239.

240.

241.

242.

243.

244.

245.

246.

247.

248.

249.

250.

251.

252.

253.

254.

255.

256.

257.

258.

259.

260.

261.

262.

263.

264.

265.

266.

267.

268.

269.

270.

271.

272.

273.

274.

275.

276.

277.

278.

279.

280.

281.

282.

283.

284.

285.

286.

287.

288.

289.

290.

291.

292.

293.

294.

295.

296.

297.

298.

299.

300.

301.

302.

303.

304.

305.

306.

307.

308.

309.

310.

311.

312.

313.

314.

315.

316.

317.

318.

319.

320.

321.

322.

323.

324.

325.

326.

327.

328.

329.

330.

331.

332.

333.

334.

335.

336.

337.

338.

339.

340.

341.

342.

343.

344.

345.

346.

347.

348.

349.

350.

351.

352.

353.

354.

355.

356.

357.

358.

359.

360.

361.

362.

363.

364.

365.

366.

367.

368.

369.

370.

371.

372.

373.

374.

375.

376.

377.

378.

379.

380.

381.

382.

383.

384.

385.

386.

387.

388.

389.

390.

391.

392.

393.

394.

395.

396.

397.

398.

399.

400.

401.

402.

403.

404.

405.

406.

407.

408.

409.

410.

411.

412.

413.

414.

415.

416.

417.

418.

419.

420.

421.

422.

423.

424.

425.

426.

427.

428.

429.

430.

431.

432.

433.

434.

435.

436.

437.

438.

439.

440.

441.

442.

443.

444.

445.

446.

447.

448.

449.

450.

451.

452.

453.

454.

455.

456.

457.

458.

459.

460.

461.

462.

463.

464.

465.

TABLE 2B R 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

94.

95.

96.

97.

98.

99.

100.

101.

102.

103.

104.

105.

106.

107.

108.

109.

110.

111.

112.

113.

114.

115.

116.

117.

118.

119.

120.

121.

122.

123.

124.

125.

126.

127.

128.

129.

130.

131.

132.

133.

134.

135.

136.

137.

138.

139.

140.

141.

142.

143.

144.

145.

146.

147.

148.

149.

150.

151.

152.

153.

154.

155.

156.

157.

158.

159.

160.

161.

162.

163.

164.

165.

166.

167.

168.

169.

170.

171.

172.

173.

174.

175.

176.

177.

178.

179.

180.

181.

182.

183.

184.

185.

186.

187.

188.

189.

190.

191.

192.

193.

194.

195.

196.

197.

198.

199.

200.

201.

202.

203.

204.

205.

206.

207.

208.

209.

210.

211.

212.

213.

214.

215.

216.

217.

218.

219.

220.

221.

222.

223.

224.

225.

226.

227.

228.

229.

230.

231.

232.

233.

234.

235.

236.

237.

238.

239.

240.

241.

242.

243.

244.

245.

246.

247.

248.

249.

250.

252.

252.

253.

254.

255.

256.

257.

258.

259.

260.

261.

262.

263.

264.

265.

266.

267.

268.

269.

270.

271.

272.

273.

274.

275.

276.

277.

278.

279.

280.

281.

282.

283.

284.

285.

286.

287.

288.

289.

290.

291.

292.

293.

294.

295.

296.

297.

298.

299.

300.

301.

302.

303.

304.

305.

306.

307.

308.

309.

310.

311.

312.

313.

314.

315.

316.

317.

318.

319.

320.

321.

322.

323.

324.

325.

326.

327.

328.

329.

330.

331.

332.

333.

334.

335.

336.

337.

338.

339.

340.

341.

342.

343.

344.

345.

346.

347.

348.

349.

350.

351.

352.

353.

354.

355.

356.

357.

358.

359.

360.

361.

362.

363.

364.

365.

366.

367.

368.

369.

370.

371.

372.

373.

374.

375.

376.

377.

378.

379.

380.

381.

382.

383.

384.

385.

386.

387.

388.

389.

390.

391.

392.

393.

394.

395.

396.

397.

398.

399.

400.

401.

402.

403.

404.

405.

406.

407.

408.

409.

410.

411.

412.

413.

414.

415.

416.

417.

418.

419.

420.

421.

422.

423.

424.

425.

426.

427.

428.

429.

430.

431.

432.

433.

434.

435.

436.

437.

438.

439.

440.

441.

442.

443.

444.

445.

446.

447.

448.

449.

450.

451.

452.

453.

454.

455.

456.

457.

458.

459.

460.

461.

462.

463.

464.

465.

466.

467.

468.

469.

470.

471.

472.

473.

474.

475.

476.

477.

478.

479.

480.

481.

482.

483.

484.

485.

486.

487.

488.

489.

490.

491.

492.

493.

494.

495.

496.

497.

498.

499.

500.

501.

502.

503.

504.

505.

506.

507.

508.

509.

510.

511.

512.

513.

514.

515.

516.

517.

518.

519.

520.

521.

522.

523.

524.

525.

526.

527.

528.

529.

530.

531.

532.

533.

534.

535.

536.

537.

538.

539.

540.

541.

542.

543.

544.

545.

546.

547.

548.

549.

550.

551.

552.

553.

554.

555.

556.

557.

558.

559.

560.

561.

562.

563.

564.

565.

566.

567.

568.

569.

570.

571.

572.

573.

574.

575.

576.

577.

578.

579.

580.

581.

582.

583.

584.

585.

586.

587.

588.

589.

590.

591.

592.

593.

594.

595.

596.

597.

598.

599.

600.

601.

602.

603.

604.

605.

606.

607.

608.

609.

610.

611.

612.

613.

614.

615.

616.

617.

618.

619.

620.

621.

622.

623.

624.

625.

626.

627.

628.

629.

630.

631.

632.

TABLE 3B R 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

94.

95.

96.

97.

98.

99.

100.

101.

102.

103.

104.

105.

106.

107.

108.

109.

110.

111.

112.

113.

114.

115.

116.

117.

118.

119.

120.

121.

122.

123.

124.

125.

126.

127.

128.

129.

130.

131.

132.

133.

134.

135.

136.

137.

138.

139.

140.

141.

142.

143.

144.

145.

146.

147.

148.

149.

150.

151.

152.

153.

154.

155.

156.

157.

158.

159.

160.

161.

162.

163.

164.

165.

166.

167.

168.

169.

170.

171.

172.

173.

174.

175.

176.

177.

178.

179.

180.

181.

182.

183.

184.

185.

186.

187.

188.

189.

190.

191.

192.

193.

194.

195.

196.

197.

198.

199.

200.

201.

202.

203.

204.

205.

206.

207.

208.

209.

210.

211.

212.

213.

214.

215.

216.

217.

218.

219.

220.

221.

222.

223.

224.

225.

226.

227.

228.

229.

230.

231.

232.

233.

234.

235.

236.

237.

238.

239.

240.

241.

242.

243.

244.

245.

246.

247.

248.

249.

250.

251.

252.

253.

254.

255.

256.

257.

258.

259.

260.

261.

262.

263.

264.

265.

266.

267.

268.

269.

270.

271.

272.

273.

274.

275.

276.

277.

278.

279.

280.

281.

282.

283.

284.

285.

286.

287.

288.

289.

290.

291.

292.

293.

294.

295.

296.

297.

298.

299.

300.

301.

302.

303.

304.

305.

306.

307.

308.

309.

310.

311.

312.

313.

314.

315.

316.

317.

318.

319.

320.

321.

322.

323.

324.

325.

326.

327.

328.

329.

330.

331.

332.

333.

334.

335.

336.

337.

338.

339.

340.

341.

342.

343.

344.

345.

346.

347.

348.

349.

350.

351.

352.

353.

354.

355.

356.

357.

358.

359.

360.

361.

362.

363.

364.

365.

366.

367.

368.

369.

370.

371.

372.

373.

374.

375.

376.

377.

378.

379.

380.

381.

382.

383.

384.

385.

386.

387.

388.

389.

390.

391.

392.

393.

394.

395.

396.

397.

398.

399.

400.

401.

402.

403.

404.

405.

406.

407.

408.

409.

410.

411.

412.

413.

414.

415.

416.

417.

418.

419.

420.

421.

422.

423.

424.

425.

426.

427.

428.

429.

430.

431.

432.

433.

434.

435.

436.

437.

438.

439.

440.

441.

442.

443.

444.

445.

446.

447.

448.

449.

450.

451.

452.

453.

454.

455.

456.

457.

458.

459.

460.

461.

462.

463.

464.

465.

466.

467.

468.

469.

470.

471.

472.

473.

474.

475.

476.

477.

478.

479.

480.

481.

482.

483.

484.

485.

486.

487.

488.

489.

490.

491.

492.

493.

494.

495.

496.

497.

498.

499.

500.

501.

502.

503.

504.

505.

506.

507.

508.

509.

510.

511.

512.

513.

514.

515.

516.

517.

518.

519.

520.

521.

522.

523.

524.

525.

526.

527.

528.

529.

530.

531.

532.

533.

534.

535.

536.

537.

538.

539.

540.

541.

542.

543.

544.

545.

546.

547.

548.

549.

550.

551.

552.

553.

554.

555.

556.

557.

558.

559.

560.

561.

562.

563.

564.

565.

566.

567.

568.

569.

570.

571.

572.

573.

574.

575.

576.

577.

578.

579.

580.

581.

582.

583.

584.

585.

586.

587.

588.

589.

590.

591.

592.

593.

594.

595.

596.

597.

598.

599.

600.

601.

602.

603.

604.

605.

606.

607.

608.

609.

610.

611.

612.

613.

614.

615.

616.

617.

618.

619.

620.

621.

622.

623.

624.

625.

626.

627.

628.

629.

630.

631.

632.

EXAMPLE 536[2S,3R,4S]-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid EXAMPLE 536A Ethyl 5,5-Dimethyl-3-oxooctanoate

Ethyl 3,3-dimethylhexanoate was prepared using the general procedure ofCahiez et al., Tetrahedron Lett., 31, 7425 (1990). To a solution of 63.8g (370 mmol) of this compound in 400 mL of ethanol, cooled to 0° C., wasadded a solution of 30 g of NaOH in 150 mL of water. The resultantsolution was warmed to ambient temperature and stirred overnight.Solvents were removed in vacuo; the residue was taken up in 700 mL ofwater, and extracted twice with 1:1 ether/hexanes. The aqueous layer wasacidified to pH3 with 1N HCl and extracted twice with hexanes. Thecombined hexane extracts were washed with brine, dried over sodiumsulfate, filtered and concentrated. A 20.2 g (150 mmol) sample of thecrude product is dissolved in 150 mL of THF; 27.3 g of1,1′-carbonyldiimidazole is added portionwise, to control gas evolution.In meantime, 33.4 g of potassium ethylmalonate and 13.4 g of magnesiumchloride are combined in 350 mL of THF (overhead mechanical stirring)and warmed to 50° C. for 3 hrs. This mixture is cooled to ambienttemperature, and the above acid imidazolide solution is added. Theresultant slurry is stirred overnight. Ether (600 mL), hexanes (600 mL)and aqueous 1N phosphoric acid (500 mL) are added, and the mixture isstirred for 30 min. The aqueous layer is separated; the organics arewashed sequentially with bicarb (2×), water and brine. The organics aredried over sodium sulfate, filtered and concentrated to give 30.2 g (95%yield) of a colorless liquid.

EXAMPLE 536B 4-Methoxy-6-(2-nitrovinyl)-1,3-benzodioxole

3-Methoxypiperonal (50.0 g) is combined with 71.9 mL of nitromethane in250 mL of acetic acid; 36 g of ammonium acetate is added, and themixture is heated to 50° C. for 4 hrs. Solvents are removed in vacuo;the residue is taken up in water and stirred for 20 min. The solution isfiltered; the filtrate is washed with water, then ether, to give 51.8 gof a yellow solid.

EXAMPLE 536C Ethyltrans,trans-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate

The compound of Example 536A (6.42 g, 30 mmol) was combined with 5.79 gof the compound of Example 536B in 40 mL of THF. DBU (0.5 mL) was added,and the mixture was. stirred at ambient temperature for 6 hrs, duringwhich time it turns reddish brown, and homogeneous. The solvents wereremoved in vacuo; the residue was taken up in EtOAc and washedsequentially with aqueous 1 N phosphoric acid and brine. The organicphase was dried over sodium sulfate, filtered and concentrated. Theresidue was dissolved in 50 mL of THF; 12 g of Raney Nickel catalyst(washed sequentially with water and ethanol) was added, followed by 10mL of acetic acid. The resultant mixture was hydrogenated under 4atmospheres of hydrogen until hydrogen uptake ceased (˜3 hrs). Thecatalyst was removed by filtration; solvents were removed in vacuo. Theresidue was dissolved in 90 mL of 2:1 ethanol/THF; 30 mg of bromoresolgreen indicator was added, followed by 30 mL of 1N sodiumcyanoborohydride in THF. Concentrated HCl was added dropwise to maintainpH at the indicator point, over 1 hr. The resultant solution was stirredovernight at ambient temperature. Bicarb was added, and the solventswere removed in vacuo; the residue was partitioned between water andEtOAc. The organic material was washed with water (2×) and brine. Theorganic phase was dried over sodium sulfate, filtered and concentrated.The crude product was dissolved in 100 mL of acetonitrile; 10 mL ofHünig's base was added, and the solution was warmed to 40° C. overnight.Removal of solvents in vacuo provided 5.0 g of a yellowish oil.

EXAMPLE 536D Ethyl[2S,3R,4S]-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate

The crude compound of Example 536C (2.0 g) was combined with 4 mL oftriethylamine in 40 mL of THF; 2.0 g of di-tert-butyldicarbonate wasadded, and the mixture was stirred at ambient temperature for 5 hrs.Solvents were removed in vacuo, and the residue was taken up in 60 mL ofethanol. Aqueous sodium hydroxide (10 mL of 2.5 N solution) was added,and the resultant solution was stirred overnight. Solvents were removedin vacuo; the residue was taken up in water and extracted with ether.The aqueous phase was acidified with aqueous 1N phosphoric acid andextracted with EtOAc. The organic extracts were washed with brine, driedover sodium sulfate, filtered, and concentrated to give 1.0 g of acolorless oil. A sample of this material (0.734 g, 1.58 mmol) wascombined with 0.35 g of pentafluorophenol and 0.364 g of EDAC in 5 mL ofDMF. The resultant solution was stirred at ambient temperature for 1 hr,then was poured onto 50 mL of 0.6M sodium bicarbonate solution andextracted (3×15 mL) with ether. The combined ether extracts were washedwith brine, dried over magnesium sulfate, filtered, and concentrated invacuo to give a foam, which was dissolved in 5 mL of THF and cooled to0° C. Simultaneously, 0.418 g (2.37 mmol) of R-4-benzyl-2-oxazolidinonewas combined with ˜0.1 mg of pyreneacetic acid in 5 mL of THF and cooledto 0° C. N-butyllithium (1.6M in hexanes) was added to a red endpoint(persists ˜10 sec), and the solution was stirred for 10 min. Thesolution was transferred into the solution of the pentafluorophenylester, and the resultant solution was stirred at 0° C. for 40 min.Solvents were removed in vacuo; the residue was taken up in bicarb andextracted with ether (3×10 mL). The combined ether extracts were washedwith brine, dried over magnesium sulfate, filtered, and concentrated invacuo. The crude mixture of diasteromeric products was separated byflash chromatography on silica gel, eluting with a gradient from4:1->3:1->2:1 hexanes/EtOAc, giving 423 mg of the faster-moving and 389mg of the slower-moving diastereomer, respectively. The faster-movingdiastereomer was dissolved in 2 mL of a 2.0M solution of sodiummethoxide in methanol (freshly prepared, containing 5% methyl formate byvolume) and stirred at ambient temperature for 16 hrs. Solvents wereremoved in vacuo, and the residue was partitioned between ether andaqueous 1N sodium hydroxide. The ether layer was washed with brine,dried over magnesium sulfate, filtered, and concentrated in vacuo. Theresidue was purified by flash chromatography on silica gel, eluting with4:1 hexanes/EtOAc. The resultant material was dissolved in 5 mL of TFAand stirred at ambient temperature for 1 hr. Solvents were removed invacuo; the residue was suspended in bicarb and extracted with EtOAc. Theorganic phase was washed with brine, dried over magnesium sulfate,filtered, and concentrated in vacuo to give 98 mg of product.

EXAMPLE 536E[2S,3R,4S]-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

The compound of Example 536D (48 mg) was combined with 35 mg of thecompound of Example 501A in 3 mL of acetonitrile; 0.5 mL of Hünig's basewas added, and the solution was allowed to stir overnight at ambienttemperature. Solvents were removed in vacuo; the residue was partitionedbetween EtOAc and aqueous 1N phosphoric acid. The organic layer waswashed with bicarb. and brine, then dried over sodium sulfate, filteredand concentrated. The residue was purified by flash chromatography onsilica gel, eluting with 2:1 hexanes/EtOAc. The product was dissolved in4 mL of ethanol; 1 mL of 2.5N aqueous sodium hydroxide was added, andthe resultant solution was stirred overnight at ambient temperature.Solvents were removed in vacuo; the residue was taken up in water andextracted with ether. The aqueous phase was acidified to pH 3 withaqueous 1N phosphoric acid and extracted with EtOAc. The organicextracts were washed with brine, dried over sodium sulfate, filtered andconcentrated to give a colorless oil. Lyophilization fromacetonitrile/0.1% aqueous TFA gave 56 mg of a white solid. ¹H NMR(CDCl₃, 300 MHz) d 0.81 (s, 3H), 0.84 (s, 3H), 0.86 (t, J =6.9 Hz, 3H),0.93 (t, J =6.9 Hz, 3H), 0.96 (t, J=6.9 Hz, 3H), 1.09-1.38 (m, 8H),1.45-1.59 (m, 4H), 1.84-2.00 (m, 2H), 3.15 (dd, J =6.9 Hz, 10.0 Hz, 2H),3.30-3.42 (m, 3H), 3.72 (t, J =10.5 Hz, 1H), 3.86 (t, J =10.5 Hz, 1H),3.88 (s, 3H), 4.02 (q, J =10.0 Hz, 1H), 4.12 (d, J =16.8 Hz, 1H), 4.29(d, J=16.8 Hz, 1H), 4.41 (brm, 1H), 5.94 (s, 1H), 6.52 (d, J =1.8 Hz,1H), 6.67 (d, J=1.8 Hz, 1H). MS (ESI) (M+H)⁺ at m/e 533. Anal calcd forC₃₀H₄₈N₂O₆.0.7 TFA: C, 61.57; H, 8.01; N, 4.57. Found: C, 61.59; H,8.20; N, 4.63.

EXAMPLE 537[2S,3R,4S]-2-(2,2-Dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid EXAMPLE 537A Ethyltrans,trans-2-(2,2-Dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate

Prepared according to the procedures of Example 536C above, substitutingthe compound of Example 501B (5-(2-nitrovinyl)-1,3-benxodioxole) for4-methoxy-6-(2-nitrovinyl)-1,3-benzodioxole.

EXAMPLE 537B Ethyl[2S,3R,4S]-2-(2,2-Dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate

The compound of Example 537A (6.8 g) was dissolved in 100 mL of ether; asolution of 1.6 g of (S)-(+)-mandelic acid in 60 mL of ether was added,the total volume was made up to ˜200 mL, and the solution was seeded.The mixture was stirred slowly overnight. The resultant crystals werecollected by filtration and recrystallized from ether/EtOAc to give 1.8g of a white solid. This material was partitioned between bicarb andether; the ether layer was washed with brine, dried over sodium sulfate,filtered, and concentrated in vacuo to give the enantiomerically pureproduct (>98% e.e.).

EXAMPLE 537C[2S,3R,4S]-2-(2,2-Dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylicAcid

Prepared from the compound of Example 537B according to the proceduresof Example 536E. ¹H NMR (CDCl₃, 300 MHz) d 0.80-0.99 (m, 15H), 1.10-1.37(m, 8H), 1.43-1.58 (m, 4H), 1.77-1.97 (m, 2H), 3.48-3.12 (m, 5H),3.60-3.69 (m, 1H), 3.75-3.86 (m, 1H), 3.95-4.16 (m, 2H), 4.28-4.4 (m,2H), 5.94 (s, 2H), 6.74 (d, J=7.8 Hz, 1 H), 6.8 (dd, J=8.1, 1.5 Hz, 1H),6.87 (d, J=1.8 Hz, 1H). MS (APCl+) m/e 503 (M+H)⁺.

EXAMPLE 538[2S,3R,4S]-2-(2,2-Dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-1-((N-propoxy,N-(n-butyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic Acid EXAMPLE538A N-Boc-N-butyl-O-allylhydroxylamine

O-Allylhydroxylamine hydrochloride hydrate (5.0 g) was dissolved in THF(15 mL). The solution was cooled to 0° C. in an ice bath.Diisopropylethylamine (8 mL) and di-t-butyldicarbonate (10.0 g) wereadded. The mixture was stirred at 0° C. for one hour at which point thebath was removed and the reaction allowed to warm to room temperatureand stirred overnight. The THF was removed in vacuo and the residuetaken up in EtOAc (25 mL), and washed with water (1×50 mL), saturatedsodium bicarbonate solution (3×50 mL), 1N phosphoric acid (3×50 mL), andbrine (1×50 mL). The organic layer was dried with sodium sulfate andevaporated to give a light yellow oil (6.5 g). This crude product wasdissolved in dry THF (25 mL) and the solution cooled to 0° C. in an icebath. Sodium hydride (1.5 g, 60% dispersion in oil) was addedportionwise over five minutes. The resulting mixture was stirred for 30minutes at 0° C. 1-Iodobutane (4.1 mL) was added dropwise to themixture. The reaction was stirred at 0° C. for one hour, then stirredovernight at room temperature. The THF was removed in vacuo and theresidue taken up in EtOAc (50 mL) and washed with water (1×50 mL),saturated sodium bicarbonate solution (3×50 mL), 1N phosphoric acid(3×50 mL), and brine (1×50 mL). The organic layer was dried with sodiumsulfate and evaporated to give a light yellow oil, which was purified byflash chromatography on silica gel eluting with 5% EtOAc/hexanes to givethe title compound as a colorless oil (6.0 g).

EXAMPLE 538B N-butyl-N-propoxyamine Trifluoroacetate

The compound of Example 538A (6.0 g) was dissolved in EtOAc (100 mL).10% Palladium-on-carbon (0.5 g) was added, and the mixture was purgedwith nitrogen. The nitrogen line was exchanged for a balloon ofhydrogen, and the mixture was stirred at room temperature for 6 hours.The catalyst was removed by filtration through a pad of Celite is andthe solvents were removed in vacuo to give a yellow oil which waspurified by flash chromatography on silica gel eluting with 5%EtOAc/hexanes to give a colorless oil (5.8 g). A sample of the resultantmaterial (1.15 g) was dissolved in CH₂Cl₂ (5 mL) and cooled in an icebath. Trifluoroacetic acid (3mL) was added and the solution stirred coldfor two hours. The solvent was removed in vacuo , care being taken notto allow the solution to warm above room temperature. The residuecontained considerable TFA and was used without further purification.

EXAMPLE 538C N-Butyl-N-propoxy-bromoacetamide

The salt of Example 538B (0.60 g) was dissolved in acetonitrile (5 mL)and cooled to −20° C. Hünig's base (5.5 mL) was added slowly.Bromoacetyl bromide (0.5 mL) was added dropwise over five minutes. Thesolution was stirred at −20° C. for 30 minutes. The bath was removed andthe solution was stirred for six hours at room temperature. The solventwas removed in vacuo and the residue taken up in EtOAc (50 mL) andwashed with water (1×25 mL), 1N phosphoric acid (3×25 mL), and brine(1×25 mL). The organic layer was dried with sodium sulfate andevaporated to give a dark orange oil (0.65 g) which was used withoutfurther purification.

EXAMPLE 538D[2S,3R,4S]-2-(2,2-Dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-1-((N-propoxy,N-(n-butyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic Acid

The compound of Example 537B was reacted with the compound of Example538C according to the procedures of Example 536E.

EXAMPLE 539[2S,3R,4S]-2-(2,2-Dimethylpentyl)-4-(1.3-benzodioxol-5-yl)-1-((N-propoxy.N-(n-propyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic Acid EXAMPLE539A N-Propyl-N-propoxy Bromoacetamide

Prepared according to the procedures of Example 538A-C, substitutingiodopropane for iodobutane in Example 538A.

EXAMPLE 539B[2S,3R,4S]-2-(2,2-Dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-1-((N-propoxy,N-(n-propyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic Acid

The compound of Example 537B was reacted with the compound of Example539A according to the procedures of Example 536E.

EXAMPLE 540[2S,3R,4S]-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-((N-propoxy,N-(n-butyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic Acid

The compound of Example 536D was reacted with the compound of Example538C according to the procedures of Example 536E.

EXAMPLE 541[2S,3R,4S]-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-((N-propoxy,N-(n-propyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic Acid

The compound of Example 536D was reacted with the compound of Example539A according to the procedures of Example 536E.

EXAMPLE 542[2S,3R,4S]-2-(2,2-Dimethylpent-3-enyl)-4-(1,3-benzodioxol-5-yl)-1-((N-propoxy,N-(n-butyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic Acid EXAMPLE542A trans-Ethyl 3,3-Dimethyl-4-hexenoate

A mixture of 4-methyl-3-penten-2-ol (7.4 g, 74 mmol), triethylorthoacetate (13.6 mL, 74 mmol) and propionic acid (0.28 mL, 3.7 mmol)was heated at 150° C. for 7 hr. The product was then distilled undernormal pressure (200-220° C.) to give 5.0 g of crude ester as acolorless oil.

EXAMPLE 542B Ethyltrans,trans-2-(2,2-Dimethylpent-3-enyl)-4-(1.3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate

The title compound is prepared according to the procedures of Examples536A and 536C, substituting the compound of Example 542A for ethyl3,3-dimethylhexanoate in Example 536A and the compound of Example 501B(5-(2-nitrovinyl)-1,3-benxodioxole) for4-methoxy-6-(2-nitrovinyl)-1,3-benzodioxole in Example 536C.

EXAMPLE 542C Ethyl[2S,3R,4S]-2-(2,2-Dimethylpent-3-enyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate

The compound of Example 542B was resolved according to the proceduredescribed in Example 537B.

EXAMPLE 542D[2S,3R,4S]-2-(2,2-Dimethylpent-3-enyl)-4-(1,3-benzodioxol-5-yl)-1-((N-propoxy,N-(n-butyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic Acid

The compound of Example 542C was reacted with the compound of Example538C according to the procedures of Example 536E.

EXAMPLE 543[2S,3R,4S]-2-(2,2-Dimethylpent-3-enyl)-4-(1,3-benzodioxol-5-yl)-1-((N-propoxym,N-(n-propyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic Acid

The compound of Example 542C was reacted with the compound (of Example539A according to the procedures of Example 536E.

EXAMPLE 544[2S,3R,4S]-2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-((N-propoxy,N-(n-butyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic Acid EXAMPLE544A Ethyltrans,trans-2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate

The title compound is prepared according to the procedures of Examples536A and 536C, substituting the compound of Example 542A for ethyl3,3-dimethylhexanoate in Example 536A.

EXAMPLE 544B Ethyl[2S,3R,4S]-2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate

The compound of Example 544A was resolved according to the proceduredescribed in Example 536D.

EXAMPLE 544C[2S,3R,4S]-2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-((N-propoxy,N-(n-butyl))aminogarbonylmethyl)-pyrrolidine-3-carboxylic Acid

The compound of Example 544B was reacted with the compound of Example538C according to the procedures of Example 536E.

EXAMPLE 545[2S,3R,4S]-2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-((N-propoxy,N-(n-propyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic Acid

The compound of Example 544B was reacted with the compound of Example539A according to the procedures of Example 536E.

EXAMPLE 546[2S,3R,4S]-2-(2-(2-pyridyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[[N-4-heptyl-N-(2-methyl-3-fluorophenyl)]aminocarbonylmethyl]-pyrrolidine-3-carboxylic Acid EXAMPLE 546A Ethyltrans,trans-2-(2-(2-pyridyl)ethyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate

The title compound is prepared according to the procedures of Examples536A and 536C, substituting the compound of Example 519A for3,3-dimethylhexanoic acid in Example 536A.

EXAMPLE 546B Ethyl[2S,3R,4S]-2-(2-(2-pyridyl)ethyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate

The compound of Example 546A (1.5 g) was dissolved in CH₂Cl₂ (25 mL).Di-t-butyldicarbonate (0.9 g) was added and the solution stirredovernight at room temperature. The solvent was evaporated in vacuo andthe residue taken up in EtOAc (50 mL), washed with water (1×50 mL),saturated sodium bicarbonate solution (3×50 mL), and brine (1×50 mL).The organic layer was dried with sodium sulfate and evaporated in vacuato give an oil with was purified by flash chromatography on silica geleluting with 1/10/10 EtOH/EtOAc/hexanes to give a colorless oil (1.5 g).The oil was dissolved in EtOH (10 mL) and 50% NaOH solution (0.5 mL) andwater (5 mL) were added. The mixture was stirred overnight at roomtemperature. The solvents were evaporated in vacuo and the residue takenup in EtOAc (25 mL) and acidified with 1 N H₃PO₄ (10 mL). The layerswere separated and the organic layer dried with sodium sulfate andevaporated to give a white semi-solid (1.3 9). A sample of the resultantBoc-protected amino acid (0.9 g) was dissolved in DMF (5 mL).(S)-Phenylalaninol (0.32 g), HOOBt (0.33 g), and EDCl (0.40 g) wereadded and the solution stirred overnight at room temperature. Water (50mL) was added and the mixture extracted with EtOAc (3×25 mL). Theorganic layers were combined, washed with water (2×50 mL), saturatedsodium bicarbonate solution (3×50 mL), and brine (1×50 mL), andevaporated to give a yellow oil; tlc indicated the presence of twodiastereomeric products. The diastereomeric amides were separated byflash chromatography on silica gel eluting with 1/12/12EtOH/EtOAc/hexanes to give faster-(450 mg) and slower-moving isomers(400 mg). The faster-moving diastereomer (400 mg) was taken up in 6N HCland heated at reflux overnight. The solvent was evaporated and theresidue was taken up in toluene (75 mL) and evaporated. This wasrepeated two additional times to give a brown solid, which was dissolvedin EtOH (50 mL). 4N HCl/dioxane (10 mL) was added and the solutionheated at reflux overnight. The EtOH was evaporated and the residuetaken up in EtOAc which was treated with saturated sodium bicarbonatesolution (3×50 mL), and brine (1×50 mL), and evaporated to give a brownsolid. Flash chromatography on silica gel eluting with 30% EtOH/EtOAcgave a mixture of products (130mg) which was approximately 70% desiredmaterial. This product was carried forward without additionalpurification.

EXAMPLE 546C[2S,3R,4S]-2-(2-(2-pyridyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[[N-4-heptyl-N-2-methyl-3-fluorophenyl)]aminocarbonylmethyl]-pyrrolidine-3-carboxylic Acid

The compound of Example 546B was reacted with the compound of Example508E according to the procedures of Example 536E.

EXAMPLE 547[2S,3R,4S]-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicAcid EXAMPLE 547A N-butyl-4-hydroxybutyramide

To 30 mL (390 mmol) of g-butyrolactone was added 45 ml (455 mmol) ofn-butylamine. The solution was heated at 85° C. for 1.5 hr, then theexcess n-butylamine was removed in vacuo. The product crystallized onstanding to give about 62 g of a colorless, low melting solid.

EXAMPLE 547B N-butyl-4-hydroxybutyl Chloroacetamide

To an ice cooled solution of 3.40 g (91.9 mmol) of LiAIH₄ in 90 mL ofTHF was added 2.4 mL of 98% H₂SO₄, dropwise, with stirring. Afterbubbling had ceased, a solution of 4.7 g of the compound of Example 547Ain 10 mL of THF was added. The mixture was stirred at reflux for 24 hr,then cooled with an ice bath and quenched by sequential dropwiseaddition of 1.7 mL H₂O, and 17 mL of 25% w/v aqueous NaOH. The whiteprecipitate was filtered, and washed with about 50 mL of THF. Thecombined filtrate and washings were concentrated to 3.85 g of an oil. Toan ice cooled solution of this material in 35 mL of ethyl acetate wasadded a solution of 5.0 g (29.2 mmol) of chloroacetic anhydride in 10 mLof ethyl acetate. The solution was stirred at 0° C. for 30 min, thenextracted with saturated aqueous NaHCO₃ solution (1×25 mL), 2M NaOH(1×25 mL), 5% NH₄OH (1×25 mL), 1M HCl (1×25 mL), and brine (1×25 mL),dried over MgSO₄, filtered, and concentrated in vacuo to an oil. Theproduct was purified via silica gel chromatography, eluting with 98:2diethyl ether: methanol, to give 1.52 g (31%) of a colorless oil.

EXAMPLE 547C Ethyl[2S,3R,4S]-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-hydroxybutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylate

To 1.52 g (6.85 mmol) of the compound of Example 547B was added 2.75 g(7.44 mmol) of the ethyl[2S,3R,4S]-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate(prepared by neutralization of the compound of Example 501G), 10 mL ofDMSO, and 2 mL of N,N-diisopropylethylamine. The solution was stirred atambient temperature for 22 h, then poured into 100 mL of water andextracted with diethyl ether (3×25 mL). The combined ether layers werewashed with water (1×25 mL), 4% (v/v) H₃PO₄ (1×25 mL), saturated aqueousNaHCO₃ solution (1×25 mL), and brine (1×25 mL), dried over MgSO₄,filtered, and concentrated to an oil. This was purified via silica gelchromatography, eluting with 98:2 diethyl ether: methanol to give 3.0 g(79%) of a colorless oil.

EXAMPLE 547D Ethyl[2S,3R,4S]-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-bromobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylate

To an ice cooled solution of 2.80 g (5.05 mmol) of the compound ofExample 547C in 27 mL of diethyl ether was added 1.4 mL (10 mmol) oftriethylamine, then 0.58 mL of methanesulfonyl chloride. A whiteprecipitate formed, and the suspension was stirred at 0° C. for 20 min.The reaction was diluted with 75 mL of diethyl ether, then extractedwith saturated aqueous NaHCO₃ solution (2×25 mL), 5% NH4OH (2×25 mL),and brine (1×25 mL), dried over MgSO₄, filtered, and concentrated to 3.0g of a colorless oil. To this material in 45 mL of DMF was added 6.0 g(69 mmol) of LiBr. The reaction warmed to about 50° C., then graduallycooled. The solution was stirred at ambient temperature for 4 h, thenpoured into 450 mL of water, and extracted with diethyl ether (3×100mL). The combined ether layers were back extracted with water (1×100mL), and brine (1×100 mL), dried over MgSO₄, filtered, and concentratedin vacuo to an oil. The product was purified via silica gelchromatography, eluting with 3:1 diethyl ether: petroleum ether, to give2.65 g (90%) of a colorless oil.

EXAMPLE 547E[2S,3R,4S]-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicAcid

To a solution of the compound of Example 547D (0.825 g, 1.34 mmol) in 3mL of ethanol was added 5 mL of 4.07M dimethylamine in ethanol; theresultant solution was heated at reflux for 75 min. Solvents wereremoved in vacuo. The residue was purified by flash chromatography onsilica gel, eluting with 9:1 dichloromethane/methanol. The resultantmaterial was taken up in 5 mL of 1.4N NaOH in 5:1 ethanol/water andstirred at ambient temperature for 14 hrs. Solvents were removed invacuo; the residue was taken up in water, then adjusted to pH 6-7 with1M HCl (˜7 mL required). The mixture was extracted with EtOAc (3×); theaqueous layer was concentrated in vacuo. The residue was washed 3× withacetonitrile; the combined washes were filtered through Celite andconcentrated to give 596 mg of a white foam.

EXAMPLE 548[2S,3R,4S]-2-(2,2-Dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicAcid

Prepared according to the procedures of Example 547, substituting thecompound of Example 537B (ethyl[2S,3R,4S]-2-(2,2-Dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate)in Example 547C.

EXAMPLE 549[2S,3R,4S]-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicAcid

Prepared according to the procedures of Example 547, substituting thecompound of Example 536D (ethyl[2S,3R,4S]-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate)in Example 547C.

EXAMPLE 550[2S,3R,4S]-2-(2,2-Dimethylpent-3-enyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicAcid

Prepared according to the procedures of Example 547, substituting thecompound of Example 542C (ethyl[2S,3R,4S]-2-(2,2-Dimethylpent-3-enyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate)in Example 547C.

EXAMPLE 551[2S,3R,4S]-2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicAcid

Prepared according to the procedures of Example 547, substituting thecompound of Example 544A (ethyl[2S,3R,4S]-2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate)in Example 547C.

EXAMPLE 552[2S,3R,4S]-2-(2,2-Dimethylpent-3-enyl)-4-(1,3-benzodioxol-5-yl)-1-[(N,N-di(nbutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylicAcid

Prepared according to the procedures of Example 1, substituting thecompound of Example 541C(ethyl[2S,3R,4S)-2-(2,2-Dimethylpent-3-enyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate).

EXAMPLE 553[2S,3R,4S]-2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N,N-di(n-butyl)aminocarbonylmethyl]-pyrrolidine-3-carboxylicAcid

Prepared according to the procedures of Example 1, substituting thecompound of Example 544B (ethyl[2S,3R,4S]-2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate).

As an indication that the compounds described herein act through bindingto endothelin receptors, the compounds have been evaluated for theirability to displace endothelin from its receptor.

As an indication that the compounds described herein act through bindingto endothelin receptors, the compounds have been evaluated for theirability to displace endothelin from its receptor.

Binding Assay ET_(A) Receptor

Preparation of Membranes from MMQ Cells:

MMQ [MacLeod/MacQueen/Login cell line (prolactin secreting rat pituitarycells)] cells from 150 mL culture flasks were collected bycentrifugation (1000×g for 10 min) and then homogenized in 25 mL of 10mM Hepes (pH 7.4) containing 0.25 M sucrose and protease inhibitors [3mM EDTA, 0.1 mM PMSF, and 5 μg/mL Pepstatin A] by a micro ultrasoniccell disrupter (Kontes). The mixture was centrifuged at 1000×g for 10min. The supernatant was collected and centrifuged at 60,000×g for 60min. The precipitate was resuspended in 20 mM Tris, pH 7.4 containingthe above protease inhibitors and centrifuged again. The final pelletwas resuspended in 20 mM Tris, pH 7.4 containing protease inhibitors andstored at −80° C. until used. Protein content was determined by theBio-Rad dye-binding protein assay.

[¹²⁵I]ET-1 Binding to Membranes:

Binding assays were performed in 96-well microtiter plates pretreatedwith 0.1% BSA. Membranes prepared from cells were diluted ˜100 fold inBuffer B (20 mM Tris, 100 mM NaCl, 10 mM MgCl₂, pH 7.4, with 0.2% BSA,0.1 mM PMSF, 5 μg/mL Pepstatin A, 0.025% bacitracin, and 3 mM EDTA) to afinal concentration of 0.2 mg/mL of protein. In competition studies,membranes (0.02 mg) were incubated with 0.1 nM of (¹²⁵I]ET-1 in Buffer B(final volume: 0.2 mL) in the presence of increasing concentrations ofunlabeled ET-1 or a test compound for 4 hours at 25° C. Afterincubation, unbound ligands were separated from bound ligands by avacuum filtration method using glass-fiber filter strips in PHD cellharvesters (Cambridge Technology, Inc., Massachusetts), followed bywashing the filter strips with saline (1 mL) for three times.

Nonspecific binding was determined in the presence of 1 μM ET-1. Thedata are shown in Table 4. The per cent inhibition at a concentration of1 mM is shown. The data show that the compounds of the invention bind tothe endothelin receptor.

TABLE 4 Binding Data % Inhibition Example of ET_(A) at 1 μM  1D 96.4  258.4  3 42.2  4 78.2  5 95.1  6B 34.9  7 63.4  8 53.7  9 69.2  10 66.1 14 86.6  15 84.8  16 96.0  17 73.9  18 97.3  19 90.3  20 80.9  21 56.3 22 86.3  23 85.9  26 83.0  27 61.2  28 63.8  29 85.3  30 80.0  31B 93.6 34 95.5  35 91.8  36 94.5  37 47.9  38 100.0  39 83.6  40 94.8  41 89.9 42 95.2  43 99.2  44 91.3  45 85.4  46 90.4  47 95.1  48 96.3  52 84.0 54 64.6  55 50.5  56 34.3  57 93.2  58 81.9  59 70.8  60 42.8  61C 90.6 62 94.1  63 92.0  64 95.0  65 82.8  66 87.7  67 96.3  68 84.6  69D 37.4 70 62.7  71 81.4  72C 80.7  73C 96.3  74 95.6  75C 95.3  76 93.1  79100.4  80 89.4  82 90.3  83 85.0  84 65.3  86 52.6  87 62.4  88 84.3  8984.6  91C 91.6  92C 107.4  93C 59.2  95D 82.1  96 86.1  97 89.0  98 86.8 99 92.1 100 76.8 101 89.2 102 75.2 103 69.0 104 98.0 105 98.6 106 90.0107 97.2 109 96.8 110 94.4 111 101.8 112 94.9 113 94.3 114 86.2 115 88.4116 79.3 117 95.2 118 93.2 119 86.6 120 99.5 121 98.6 122 95.3 125 97.2126 91.7 127 91.4 128 95.4 123 89.7 124 91.0 129 100.1 130 91.0 131 89.5132 90.0 133 88.6 134 92.2 135B 77.7 136 79.4 138 83.0 139 98.6 140106.3 141 92.8 142B 78.7 143 20.6 144 78.2 145 32.4 146 25.0 147 73.0148 94.7 149 84.6 150 93.6 151 80.5 152 86.9 153 97.1 154 80.2 155 92.7156 92.6 157 83.8 158 91.8 159 36.2 160B 80.3 161 93.6 162B 91.5 16390.6 164 98.6 165 54.1 166 91.6 167 94.4 291 100.0 293 89.8 294 77.7 29593.0 296 87.1 297 84.4 298 93.3 299 90.4 300 96.1 301 96.7 302 86.6 30387.2 304 89.7 305 87.4 306 93.3 307 92.2 308 93.0 309 80.7 310 87.1 31192.3 312 88.2 313 96.3 314 86.0 315 82.7 316 74.0 317 68.5 318 79.0 31979.0 320 82.2 322 95.6 323 91.3 324 95.0 334 88.0 335 84.1 340 94.0 34187.4 342 89.9 343 98.7 344 95.6 345 86.6 346 88.9 348 91.3 349 73.0 35092.1 351 99.0 352 96.2 353 73.7 354 79.3 355 100 356 93.5 357 96.3 35862.7 359 94.7 360 93.7 361 92.8 362 94.1 363 82.3 365 59.2 366 91.5 36771.0 368 94.6 370 84.3 371 97.2 372 91.6 373 92.9 374 91.4 375 97.8 37690.2 377 85.6 378 91.1 379 90.7 380 99.0 381 95.7 382 96.8 383 91.4 38479.4 385 86.2 386 47.8 387 98.7 388 69.2 389 100 390 98.2 391 45.6 39293.7 393 100 394 97.8 395 79.8 396 98.7 397 100 398 90.0 399 59.9 40093.0 401 96.5 402 80.5 403 96.1 404 95.4 405 86.4 406 94.5 407 100 408100 409 89.4 410 91.4 411 93.5 412 86.4 413 99.5 414 91.4 415 87.3 41686.4 417 98.7 418 100 420 100 421 100 422 96.6 423 89.1 424 85.8 42590.8 426 97.2 427 100 428 100 429 100 430 94.1 431 99.1 432 95.5 43399.6 434 100 435 97.8 436 100 437 100 438 94.3 439 94.3 440 100 441 98.3442 100 443 100 444 100 445 98.1 446 97.8 447 96.9 448 97.4 449 100.0450 99.7 451 100 452 100 453 94.4 454 96.8 455 99.1 456 95.3 457 88.9458 93.4 459 97.4 460 91.6 461 99.6 462 98.3 463 96.1 464 97.1 465 95.1466 94.2 467 93.6 468 88.7 469 98.7 470 100 471 100 475 91.6 476 82.3477 80.1 479 96.5 495 95.9 496 92.7 497 83.7 498 81.6 499 68.5 500 55.7502 95.7 503 97.0 504 97.1 505 95.8 506 99.7 507 99.3 508 97.6 509 100510 100 511 99.2 512 98.9 513 98.0 514 100 515 99.1 516 99.7 517 94.1518 96.3 519 99.1 520 97.4 521 100 523 99.0 524 99.2 525 100 526 100 52796.6 528 98.3 529 98.1 531 99.8 532 100 533 97.9 536 100 537 97.2

As further demonstration of the efficacy of the described compounds asfunctional antagonists of endothelin, the ability of the describedcompounds to inhibit ET-1-induced phosphatidylinositol hydrolysis wasmeasured.

Determination of Phosphatidylinositol (PI) Hydrolysis

MMQ cells (0.4×10⁶ cells/mL) were labeled with 10 μCi/mL of[³H]myo-inositol in RPMI for 16 hours. The cells were washed with PBS,then incubated with Buffer A containing protease inhibitors and 10 mMLiCl for 60 minutes. The cells were then incubated with test compoundsfor 5 minutes, and then challenged with 1 nM ET-1. ET-1 challenge wasterminated by the addition of 1.5 mL of 1:2 (v/v) chloroform-methanol.Total inositol phosphates were extracted after adding chloroform andwater to give final proportions of 1:1:0.9 (v/v/v)chloroform-methanol-water as described by Berridge (Biochem. J. 206587-595 (1982)). The upper aqueous phase (1 mL) was retained and a smallportion (100 μL) was counted. The rest of the aqueous sample wasanalyzed by batch chromatography using anion-exchange resin AG1-X8(Bio-Rad). The IC₅₀ is the concentration of test compound required toinhibit the ET-induced increase in PI turnover by 50%. The results ofthe above study clearly indicate that the compounds act as functional ETantagonists.

TABLE 5 Phosphatidylinositol Hydrolysis Example IC₅₀ μM  1D 0.025  140.017  15 0.010  16 0.009  18 0.009  19 0.024  30 0.001  31B 0.002  430.0001  46 0.002  47 0.0005  48 0.0004 291 0.0098 300 0.0012 534 0.05553 0.0004

Table 6 ET_(A)/ET_(B) Selectivity

MMQ cells, porcine cerebellar tissues (known to contain ETB receptors)and chinese hamster ovary cells (CHO) permanently transfected with thehuman ETA or ETB receptor were homogenized in 25 ml of 10 mM Hepes (pH7.4) containing 0.25 M sucrose and a protease inhibitor [50 mM EDTA ,0.1 mM PMSF, 5 μg/ml Pepstatin A, and 0.025% Bacitracin] using a microultrasonic cell disrupter. The mixture was centrifuged at 1000×g for 10min. The supernatant was collected and centrifuged at 60,000×g for 60min. The precipitate was resuspended in 20 mM Tris, pH 7.4 containingprotease inhibitor and centrifuged again. The final membrane pellet wasresuspended in 20 mM Tris, pH 7.4 containing protease inhibitors andstored at −80° C. until used. Protein content was determined by theBio-Rad dye-binding protein assay.

Binding assays were performed in 96-well microtiter plates pretreatedwith 0.1% BSA. Membranes prepared from cells were diluted ˜100 fold inBuffer B (20 mM Tris, 100 mM NaCl, 10 mM MgCl₂, pH 7.4, with 0.2% BSA,0.1 mM PMSF, 5 μg/mL Pepstatin A, 0.025% bacitracin, and 50 mM EDTA) toa final concentration of 0.2 mg/mL of protein. In competition bindingstudies, membranes (0.02 mg) were incubated with 0.1 nM of [125I]ET-1(for ETA assay in MMQ or CHO cells transfected with human ET_(A)receptor) or [125I]ET-3 (for ETB assay in porcine cerebellum or CHOcells transtected with human ET_(B) receptor) in Buffer B (final volume:0.2 mL) in the presence of increasing concentrations of the testcompound for 3 hours at 25° C. After incubation, unbound ligands wereseparated from bound ligands by a vacuum filtration method usingglass-fiber filter strips in PHD cell harvesters (Cambridge Technology,Inc., Massachusetts), washing the filter strips three times with saline(1 mL). Nonspecific binding was determined in the presence of 1 μM ET-1.IC50 values are calculated using an average of at least two separatedeterminations. The data shows the selectivity of the compounds of theinvention in binding to the endothelin receptors.

TABLE 6 rET-A pET-B hET-A hET-B EXAMPLE rET-A IC₅₀ IC₅₀ Selectivity IC₅₀IC₅₀ Selectivity NO. (% I @ 1 μM) (nM) (nM) (rA/pB ratio) (nM) (nM)(hA/hB ratio) 502 95.7 3.0 71,000 23,000 503 97.0 1.4 50,000 35,000 0.9252,000 56,000 504 97.1 3.1 >100,000 >32,000 4.6 >100,000 >21,000 50595.8 2.0 60,000 30,000 5.7 68,000 12,000 506 99.7 3.2 >100,000 >31,0003.0 61,000 20,000 507 99.3 3.0 >100,000 >33,000 1.63 >100,000 >60,000508 97.6 1.9 45,000 23,000 2.1 51,000 24,000 509 100 0.56 30,000 53,0000.51 23,000 45,000 510 100 0.50 35,000 68,000 1.0 11,000 11,000 511 99.20.81 N.D. — 0.60 15,000 25,000 512 98.9 0.42 >80,000 >190,000 0.5860,000 >102,000 513 98.0 0.30 8,800 29,000 0.36 14,000 37,000 514 1001.0 26,000 26,000 0.36 9,800 29,000 515 99.1 1.6 >62,000 >37,0006.7 >100,000 >15,000 516 99.7 0.71 29,000 40,000 1.8 37,000 21,000 51794.1 1.0 30,000 30,000 0.43 12,000 29,000 518 96.3 1.3 85,000 63,0000.31 38,000 124,000 519 99.1 0.38 14,000 36,000 0.23 19,000 83,000 52097.4 0.20 28,000 130,000 521 100 0.67 37,000 54,000 523 99.0 0.42 360880 0.33 290 880 524 99.2 0.79 1,700 2,100 0.82 890 1,100 525 100 8.2560 70 526 100 42 — — 17 7,400 440 527 96.6 7.9 10,000 1,300 528 98.3 1143,000 3,800 529 98.1 3.6 6,300 1,700 531 99.8 1.2 — — 0.71 870 1,200532 100 5.1 3,200 630 533 97.9 76 7,900 100 40 22,000 560 534 0.12 0.363.0 0.08 0.28 3.5 536 100 0.52 17,000 33,000 0.92 52,000 56,000 537 97.20.96 5,900 6,200 0.23 1,900 8,200 552 97.3 0.78 7100,000 7125,0001.0 >96,000 >96,000 553 100 0.26 42,400 160,000 0.29 39,500 136,000

Determination of Plasma Protein Binding

A stock solution of the test compound in 50% ethanol (2 mg/mL) wasdiluted 10× into PBS, A 0.4 mL sample of this secondary stock solutionwas added to 3.6 mL of fresh plasma, and incubated at room temperaturefor 1 hour. A 1 mL sample of this incubation mixture was transferred toa Centrifree ultrafiltration tube. The sample was centrifuged in afixed-bucket rotor for approximately 2 min and the filtrate wasdiscarded. The sample was centrifuged for another 15-30 min. A 100 μLsample of the ultrafiltratewas transfered to a micro HPLC sample vialcontaining 150 ML of HPLC mobile phase and mixed thoroughly. A 50 μLsample was injected and the concentration of drug in the ultrafiltratewas determined by HPLC analysis compared against a standard sampleprepared identically in the absence of plasma. Ultrafiltrateconcentrations are calculated from a calibration curve. Protein bindingis calculated according to the equation:

% PB=[1-(Cu/Ci)]*100%

where Cu is the ultrafiltrate concentration and Ci is the initial plasmaconcentration.

Data: Example #43 >99.5% Example #532 96.8% Example #533 82.6%

The ability of the compounds of the invention to lower blood pressurecan be demonstrated according to the methods described in Matsumura, etal., Eur. J. Pharmacol. 185 103 (1990) and Takata, et al., Clin. Exp.Pharmacol. Physiol. 10 131 (1983).

The ability of the compounds of the invention to treat congestive heartfailure can be demonstrated according to the method described inMargulies, et al., Circulation 82 2226 (1990).

The ability of the compounds of the invention to treat myocardialischemia can be demonstrated according to the method described inWatanabe, et al., Nature 344 114 (1990).

The ability of the compounds of the invention to treat coronary anginacan be demonstrated according to the method described in Heistad, etal., Circ. Res. 54 711 (1984).

The ability of the compounds of the invention to treat cerebralvasospasm can be demonstrated according to the methods described inNakagomi, et al., J. Neurosurg. 66 915 (1987) or Matsumura, et al., LifeSci. 49 841-848 (1991).

The ability of the compounds of the invention to treat cerebral ischemiacan be demonstrated according to the method described in Hara et al.,European. J. Pharmacol. 197: 75-82, (1991).

The ability of the compounds of the invention to treat acute renalfailure can be demonstrated according to the method described in Kon, etal., J. Clin. Invest. 83 1762 (1989).

The ability of the compounds of the invention to treat chronic renalfailure can be demonstrated according to the method described inBenigni, et al., Kidney Int. 44 440-444 (1993).

The ability of the compounds of the invention to treat gastriculceration can be demonstrated according to the method described inWallace, et al., Am. J. Physiol. 256 G661 (1989).

The ability of the compounds of the invention to treatcyclosporin-induced nephrotoxicity can be demonstrated according to themethod described in Kon, et al., Kidney Int. 37 1487 (1990).

The ability of the compounds of the invention to treat endotoxin-inducedtoxicity (shock) can be demonstrated according to the method describedin Takahashi, et al., Clinical Sci. 79 619 (1990).

The ability of the compounds of the invention to treat asthma can bedemonstrated according to the method described in Potvin and Varma, Can.J. Physiol. and Pharmacol. 67 1213 (1989).

The ability of the compounds of the invention to treattransplant-induced atherosclerosis can be demonstrated according to themethod described in Foegh, et al., Atherosclerosis 78 229-236 (1989).

The ability of the compounds of the invention to treat atherosclerosiscan be demonstrated according to the methods described in Bobik, et al.,Am. J. Physiol. 258 C408 (1990) and Chobanian, et al., Hypertension 15327 (1990).

The ability of the compounds of the invention to treat LPL-relatedlipoprotein disorders can be demonstrated according to the methoddescribed in Ishida, et al., Biochem. Pharmacol. 44 1431-1436 (1992).

The ability of the compounds of the invention to treat proliferativediseases can be demonstrated according to the methods described inBunchman ET and CA Brookshire, Transplantation Proceed. 23 967-968(1991); Yamagishi, et al., Biochem. Biophys. Res. Comm. 191 840-846(1993); and Shichiri, et al., J. Clin. Invest. 87 1867-1871 (1991).Proliferative diseases include smooth muscle proliferation, systemicsclerosis, cirrhosis of the liver, adult respiratory distress syndrome,idiopathic cardiomyopathy, lupus erythematosus, diabetic retinopathy orother retinopathies, psoriasis, scleroderma, prostatic hyperplasia,cardiac hyperplasia, restenosis following arterial injury or otherpathologic stenosis of blood vessels.

The ability of the compounds of the invention to treat acute or chronicpulmonary hypertension can be demonstrated according to the methoddescribed in Bonvallet et al., Am. J. Physiol. 266 H1327 (1994).Pulmonary hypertension can be associated with congestive heart failure,mitral valve stenosis, emphysema, lung fibrosis, chronic obstructivepulmonary disease (COPD), acute repiratory distress syndrome (ARDS),altitude sickness, chemical exposure, or may be idiopathic.

The ability of the compounds of the invention to treat plaletetaggregation, and thrombosis, can be demonstrated according to the methoddescribed in McMurdo et al. Eu. J. Pharmacol. 259 51 (1994).

The ability of the compounds of the invention to treat cancers can bedemonstrated according to the method described in Shichiri, et al., J.Clin. Invest. 87 1867 (1991).

The ability of the compounds of the invention to treat IL-2 (and othercytokine) mediated cardiotoxicity and vascular permeability disorderscan be demonstrated according to the method described in Klemm et al.,Proc. Nat. Acad. Sci. 92 2691 (1995).

The ability of the compounds of the invention to treat nociception canbe demonstrated according to the method described in Yamamoto et al., J.Pharmadol. Exp. Therap. 271 156 (1994).

The ability of the compounds of the invention to treat colitis can bedemonstrated according to the method described in Hogaboam et al (EUR,J. Pharmacol. 1996, 309, 261-269).

The ability of the compounds of the invention to treatischemia-repurfusion injury in kidney transplantation can bedemonstrated according to the method described in Aktan et al(Transplant Int 1996, 9, 201-207).

The ability of the compounds of the invention to treat angina, pulmonaryhypertension, raynaud's disease, and migraine can be demonstratedaccording to the method described in Ferro and Webb (Drugs 1996, 51,12-27).

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids. These salts include but are notlimited to the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as loweralkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides, and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained.

Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulphuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of the compounds of formula (I), or separately byreacting the carboxylic acid function with a suitable base such as thehydroxide, carbonate or bicarbonate of a pharmaceutically acceptablemetal cation or with ammonia, or an organic primary, secondary ortertiary amine. Such pharmaceutically acceptable salts include, but arenot limited to, cations based on the alkali and alkaline earth metals,such as sodium, lithium, potassium, calcium, magnesium, aluminum saltsand the like, as well as nontoxic ammonium, quaternary ammonium, andamine cations, including, but not limited to ammonium,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, triethylamine, ethylamine, and the like. Otherrepresentative organic amines useful for the formation of base additionsalts include diethylamine, ethylenediamine, ethanolamine,diethanolamine, piperazine and the like.

The compounds of the invention are useful for antagonizing endothelin ina human or other mammal. In addition, the compounds of the presentinvention are useful (in a human or other mammal) for the treatment ofhypertension, acute or chronic pulmonary hypertension, Raynaud'sdisease, congestive heart failure, myocardial ischemia, reperfusioninjury, coronary angina, cerebral ischemia, cerebral vasospasm, chronicor acute renal failure, non-steroidal antiinflammatory drug inducedgastric ulceration, cyclosporin induced nephrotoxicity,endotoxin-induced toxicity, asthma, fibrotic or proliferative diseases,including smooth muscle proliferation, systemic sclerosis, cirrhosis ofthe liver, adult respiratory distress syndrome, idiopathiccardiomyopathy, lupus erythematosus, diabetic retinopathy or otherretinopathies, psoriasis, scleroderma, prostatic hyperplasia, cardiachyperplasia, restenosis following arterial injury or other pathologicstenosis of blood vessels, LPL-related lipoprotein disorders,transplantation-induced atherosclerosis or atherosclerosis in general,platelet aggregation, thrombosis, cancers, prostate cancer, IL-2 andother cytokine mediated cardiotoxicity and permeability disorders, andnociception, especially treatment of bone pain associated with bonecancer.

Total daily dose administered to a host in single or divided doses maybe in amounts, for example, from 0.001 to 1000 mg/kg body weight dailyand more usually 0.1 to 100 mg/kg for oral administration or 0.01 to 10mg/kg for parenteral administration. Dosage unit compositions maycontain such amounts of submultiples thereof to make up the daily dose.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination, and the severity ofthe particular disease undergoing therapy.

The compounds of the present invention may be administered orally,parenterally, sublingually, by inhalation spray, rectally, or topicallyin dosage unit formulations containing conventional nontoxicpharmaceutically acceptable carriers, adjuvants, and vehicles asdesired. Topical administration may also involve the use of transdermaladministration such as transdermal patches or iontophoresis devices. Theterm parenteral as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection, or infusiontechniques.

Injectable preparations, for example, sterile injectable aqueous oroleagenous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-propanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter and polyethylene glycols which are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose lactose or starch. Such dosage forms may also comprise, as isnormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

The compounds of the present invention can also be administered in theform of liposomes. As is known in the art, liposomes are generallyderived from phospholipids or other lipid substances. Liposomes areformed by mono- or multi-lamellar hydrated liquid crystals that aredispersed in an aqueous medium. Any non-toxic, physiologically aceptableand metabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention,. stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andphosphatidyl cholines (lecithins), both natural and synthetic.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

A representative solid dosage form, for example, a tablet or a capsule,comprises:

Compound of the invention: 35% w/w Starch, Pregelatinized, NF 50% w/wMicrocrystalline Cellulose, NF 10% w/w Talc, Powder, USP 5% w/w

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more cardiovascular agents independently selected from diuretics,adrenergic blocking agents, vasodilators, calcium channel blockers,renin inhibitors, angiotensin converting enzyme (ACE) inhibitors,angiotensin II antagonists, potassium channel activators and othercardiovascular agents.

Representative diuretics include hydrochlorothiazide, chlorothiazide,acetazolamide, amiloride, bumetanide, benzthiazide, ethacrynic acid,furosemide, indacrinone, metolazone, spironolactone, triamterene,chlorthalidone and the like or a pharmaceutically acceptable saltthereof.

Representative adrenergic blocking agents include phentolamine,phenoxybenzamine, prazosin, terazosin, tolazine, atenolol, metoprolol,nadolol, propranolol, timolol, carteolol and the like or apharmaceutically acceptable salt thereof.

Representative vasodilators include hydralazine, minoxidil, diazoxide,nitroprusside and the like or a pharmaceutically acceptable saltthereof.

Representative calcium channel blockers include amrinone, bencyclane,diltiazem, fendiline, flunarizine, nicardipine, nimodipine, perhexilene,verapamil, gallopamil, nifedipine and the like or a pharmaceuticallyacceptable salt thereof.

Representative renin inhibitors include enalkiren, zankiren, RO 42-5892,PD-134672 and the like or a pharmaceutically acceptable salt thereof.

Representative angiotensin II antagonists include DUP 753, A-81988 andthe like.

Representative ACE inhibitors include captopril, enalapril, lisinopriland the like or a pharmaceutically acceptable salt thereof.

Representative potassium channel activators include pinacidil and thelike or a pharmaceutically acceptable salt thereof.

Other representative cardiovascular agents include sympatholytic agentssuch as methyldopa, clonidine, guanabenz, reserpine and the like or apharmaceutically acceptable salt thereof.

The compounds of the invention and the cardiovascular agent can beadministered at the recommended maximum clinical dosage or at lowerdoses. Dosage levels of the active compounds in the compositions of theinvention may be varied so as to obtain a desired therapeutic responsedepending on the route of administration, severity of the disease andthe response of the patient. The combination can be administered asseparate compositions or as a single dosage form containing both agents.

When administered as a combination, the therapeutic agents can beformulated as separate compositions which are given at the same time ordifferent times, or the therapeutic agents can be given as a singlecomposition.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds, processes,compositions and methods. Variations and changes which are obvious toone skilled in the art are intended to be within the scope and nature ofthe invention which are defined in the appended claims.

What is claimed is:
 1. A process for the preparation of a compound ofthe formula:

wherein E is a carboxy-protecting group and R₁ and R₂ are independentlyselected from loweralkyl, alkoxyalkyl, alkoxycarbonylalkyl,hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl,thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl,alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl,aminocarbonylalkenyl, alkylaminocarbonylalkenyl,dialkylaminocarbonylalkenyl, aryl, arylalkyl, aryloxyalkyl,arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoakyl, alkylsulfonylamidoalkyl,heterocyclic and (heterocyclic)alkyl; or a salt thereof, comprising a)reacting a compound of the formula:

with hydrogen and Raney nickel or a platinum catalyst to provide amixture comprising dihydropyrroles of the formula:

b) reacting the product of step a) and an acid or a mixture of acids toprovide a compound of the formula

c) reacting the product of step b) and a base.
 2. The process of claim 1wherein E is loweralkyl, R₁ is aryl and R₂ is heterocyclic.
 3. Theprocess of claim 1 wherein the hydrogenation catalyst is Raney nickeland the acid is a mixture of acetic acid and trifluoroacetic acid. 4.The process of claim 1 wherein E is loweralkyl, R₁ is 4-methoxyphenyland R₂ is 1,3-benzodioxol-5-yl.
 5. A process for the preparation of acompound of the formula:

wherein E is a carboxy-protecting group, R₁ and R₂ are independentlyselected from loweralkyl, alkoxyalkyl, alkoxycarbonylalkyl,hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl,thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl,alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl,aminocarbonylalkenyl, alkylaminocarbonylalkenyl,dialkylaminocarbonylalkenyl, aryl, arylalkyl, aryloxyalkyl,arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl,alkylsulfonylamidoalkyl, heterocyclic and (heterocyclic)alkyl and R₃ isR₄—C(O)—R₅— wherein R₅ is alkylene and R₄ is (R₁₁)(R₁₂)N— wherein R₁₁and R₁₂ are independently selected from (1) loweralkyl, (2) haloalkyl,(3) alkoxyalkyl, (4) haloalkoxyalkyl, (5) alkenyl, (6) alkynyl, (7)cycloalkyl, (8) cycloalkylalkyl, (9) aryl, (10) heterocyclic, (11)arylalkyl and (12) (heterocyclic)alkyl; (13) hydroxyalkyl, (14) alkoxy,(15) aminoalkyl, and (16) trialkylaminoalkyl, or a salt thereof,comprising a) reacting a compound of the formula:

with hydrogen and Raney nickel or a platinum catalyst to provide amixture comprising dihydropyrroles of the formula:

b) reacting the product of step a) and an acid or a mixture of acids; c)reacting the product of step b) and a base to provide a compound of theformula

d) reacting the product of step c) and a compound of the formula R₃—Xwherein X is a leaving group.
 6. The process of claim 5 wherein E isloweralkyl, R₁ is aryl, R₂ is heterocyclic and R₃ is —CH₂C(O)NR₁₁R₁₂wherein R₁₁ and R₁₂ are independently selected from the group consistingof loweralkyl.
 7. The process of claim 5 wherein the hydrogenationcatalyst is Raney nickel and the acid is a mixture of acetic acid andtrifluoroacetic acid.
 8. The process of claim 5 wherein E is loweralkyl,R₁ is 4-methoxyphenyl, R₂ is 1,3-benzodioxol-5-yl, R₃ is—CH₂C(O)N(n-Bu)₂ and X is a halogen or sulfonate leaving group.
 9. Aprocess for the preparation of the substantially pure (+)-trans,transoptical isomer of the compound of the formula:

wherein E is loweralkyl, R₁ is 4-methoxyphenyl and R2 is1,3-benzodioxol-5-yl, or a salt thereof, comprising reacting a mixtureof the (+) and (−) enantiomers of a compound of the formula:

wherein E is loweralkyl, R₁ is 4-methoxyphenyl, and R₂ is1,3-benzodioxol-5-yl, and S-(+)-mandelic acid and isolating themandelate salt of the (+)trans,trans enantiomer.